Siste publikasjoner

• Aure, Miriam Ragle; Fleischer, Thomas; Bjørklund, Sunniva; Ankill, Jørgen; Castro Mondragón, Jaime Abraham; Børresen-Dale, Anne-Lise; Tost, Jörg; Sahlberg, Kristine Kleivi; Mathelier, Anthony; Tekpli, Xavier & Kristensen, Vessela N. (2021). Crosstalk between microRNA expression and DNA methylation drives the hormone-dependent phenotype of breast cancer. Genome Medicine.  ISSN 1756-994X.  13 . doi: 10.1186/s13073-021-00880-4
• Høydahl, Lene; Frigstad, Terje; Rasmussen, Ingunn B; Øynebråten, Inger; Schjetne, Karoline W; Schjetne, Karoline Western; Andersen, Jan Terje; Michaelsen, Terje Einar; Lunde, Elin; Bogen, Bjarne & Sandlie, Inger (2021). Antibody-mediated delivery of T-cell epitopes to antigen-presenting cells induce strong CD4 and CD8 T-cell responses. Vaccine.  ISSN 0264-410X.  39(11), s 1583- 1592 . doi: 10.1016/j.vaccine.2021.02.012
• Lemma, Roza Berhanu; Ledsaak, Marit; Fuglerud, Bettina Maria; Sandve, Geir Kjetil; Eskeland, Ragnhild & Gabrielsen, Odd Stokke (2021). Chromatin occupancy and target genes of the haematopoietic master transcription factor MYB. Scientific Reports.  ISSN 2045-2322.  11(9008) . doi: 10.1038/s41598-021-88516-w Vis sammendrag

  The transcription factor MYB is a master regulator in haematopoietic progenitor cells and a pioneer factor affecting differentiation and proliferation of these cells. Leukaemic transformation may be promoted by high MYB levels. Despite much accumulated molecular knowledge of MYB, we still lack a comprehensive understanding of its target genes and its chromatin action. In the present work, we performed a ChIP-seq analysis of MYB in K562 cells accompanied by detailed bioinformatics analyses. We found that MYB occupies both promoters and enhancers. Five clusters (C1–C5) were found when we classified MYB peaks according to epigenetic profiles. C1 was enriched for promoters and C2 dominated by enhancers. C2-linked genes were connected to hematopoietic specific functions and had GATA factor motifs as second in frequency. C1 had in addition to MYB-motifs a significant frequency of ETS-related motifs. Combining ChIP-seq data with RNA-seq data allowed us to identify direct MYB target genes. We also compared ChIP-seq data with digital genomic footprinting. MYB is occupying nearly a third of the super-enhancers in K562. Finally, we concluded that MYB cooperates with a subset of the other highly expressed TFs in this cell line, as expected for a master regulator

• Grad, Iwona; Hanes, Robert; Ayuda-Durán, Pilar; Kuijjer, Marieke Lydia; Enserink, Jorrit; Meza-Zepeda, Leonardo A & Myklebost, Ola (2021). Discovery of novel candidates for anti- liposarcoma therapies by medium-scale high-throughput drug screening. PLOS ONE.  ISSN 1932-6203.  16(3) . doi: 10.1371/journal.pone.0248140 Fulltekst i vitenarkiv.
• Cunha, Eva; Chen, Xiaorui; Sanz Gaitero, Marta; Mills J, Deryck & Luecke, Hartmut (2021). Cryo-EM structure of Helicobacter pylori urease with an inhibitor in the active site at 2.0 Å resolution. Nature Communications.  ISSN 2041-1723.  12:230, s 1- 8 . doi: 10.1038/s41467-020-20485-6
• Taboada-Castro, Hermenegildo; Castro Mondragón, Jaime Abraham; Aguilar-Vera, Alejandro; Hernández-Álvarez, Alfredo José; van Helden, Jacques & Encarnación-Guevara, Sergio (2020). RhizoBindingSites, a Database of DNA-Binding Motifs in Nitrogen-Fixing Bacteria Inferred Using a Footprint Discovery Approach. Frontiers in Microbiology.  ISSN 1664-302X.  11, s 1- 11 . doi: 10.3389/fmicb.2020.567471 Fulltekst i vitenarkiv.
• Itkonen, Harri; Poulose, Ninu; Steele, Rebecca E.; Martin, Sara E.S.; Levine, Zebulon G.; Duveau, Damien Y.; Carelli, Ryan; Singh, Reema; Urbanucci, Alfonso; Loda, Massimo; Thomas, Craig J.; Mills, Ian Geoffrey & Walker, Suzanne (2020). Inhibition of O-GlcNAc transferase renders prostate cancer cells dependent on CDK9. Molecular Cancer Research.  ISSN 1541-7786.  18(10), s 1512- 1521 . doi: 10.1158/1541-7786.MCR-20-0339
• Fagny, Maud; Kuijjer, Marieke Lydia; Stam, Maike; Joets, Johann; Turc, Olivier; Rozière, Julien; Pateyron, Stéphanie; Venon, Anthony & Vitte, Clémentine (2020). Identification of Key Tissue-Specific, Biological Processes by Integrating Enhancer Information in Maize Gene Regulatory Networks. Frontiers in Genetics.  ISSN 1664-8021.  11 . doi: 10.3389/fgene.2020.606285 Fulltekst i vitenarkiv.
• Wang, Shixiong; Somisetty, Venkata Satheesh; Bai, Baoyan; Chernukhin, Igor; Niskanen, Henri; Kaikkonen, Minna; Bellet, Meritxell; Carroll, Jason S. & Hurtado, Antoni (2020). The proapoptotic gene interferon regulatory factor-1 mediates the antiproliferative outcome of paired box 2 gene and tamoxifen. Oncogene.  ISSN 0950-9232.  39, s 6300- 6312 . doi: 10.1038/s41388-020-01435-4 Fulltekst i vitenarkiv.
• Bonner, Erin R; Waszak, Sebastian Martin; Grotzer, Michael A; Mueller, Sabine & Nazarian, Javad (2020). Mechanisms of imipridones in targeting mitochondrial metabolism in cancer cells. Neuro-Oncology.  ISSN 1522-8517. . doi: https://doi.org/10.1093/neuonc/noaa283 Vis sammendrag

  ONC201 is the first member of the imipridone family of anticancer drugs to enter the clinic for the treatment of diverse solid and hematologic cancers. A subset of pediatric and adult patients with highly aggressive brain tumors has shown remarkable clinical responses to ONC201, and recently, the more potent derivative ONC206 entered clinical trials as a single agent for the treatment of CNS cancers. Despite the emerging clinical interest in the utility of imipridones, their exact molecular mechanisms are not fully described. In fact, the existing literature points to multiple pathways (e.g. TRAIL signaling, dopamine receptor antagonism, and mitochondrial metabolism) as putative drug targets. We have performed a comprehensive literature review and highlighted mitochondrial metabolism as the major target of imipridones. In support of this, we performed a meta-analysis of an ONC201 screen across 539 human cancer cell lines and showed that the mitochondrial protease ClpP is the most significant predictive biomarker of response to treatment. Herein, we summarize the main findings on the anticancer mechanisms of this potent class of drugs, provide clarity on their role, and identify clinically relevant predictive biomarkers of response.

• Gawel, Kinga Aurelia; Turski, Waldemar A.; van der Ent, Wietske; Mathai, Benan John; Kirstein-Smardzewska, Karolina Joanna; Simonsen, Anne & Esguerra, Camila V. (2020). Phenotypic Characterization of Larval Zebrafish (Danio rerio) with Partial Knockdown of the cacna1a Gene. Molecular Neurobiology.  ISSN 0893-7648.  57(4) . doi: https://doi.org/10.1007/s12035-019-01860-x Vis sammendrag

  The CACNA1A gene encodes the pore-forming α1 subunit of voltage-gated P/Q type Ca2+ channels (Cav2.1). Mutations in this gene, among others, have been described in patients and rodents suffering from absence seizures and episodic ataxia type 2 with/without concomitant seizures. In this study, we aimed for the first time to assess phenotypic and behavioral alterations in larval zebrafish with partial cacna1aa knockdown, placing special emphasis on changes in epileptiform-like electrographic discharges in larval brains. Whole-mount in situ hybridization analysis revealed expression of cacna1aa in the optic tectum and medulla oblongata of larval zebrafish at 4 and 5 days post-fertilization. Next, microinjection of two antisense morpholino oligomers (individually or in combination) targeting all splice variants of cacna1aa into fertilized zebrafish eggs resulted in dose-dependent mortality and decreased or absent touch response. Over 90% knockdown of cacna1aa on protein level induced epileptiform-like discharges in the optic tectum of larval zebrafish brains. Incubation of morphants with antiseizure drugs (sodium valproate, ethosuximide, lamotrigine, topiramate) significantly decreased the number and, in some cases, cumulative duration of epileptiform-like discharges. In this context, sodium valproate seemed to be the least effective. Carbamazepine did not affect the number and duration of epileptiform-like discharges. Altogether, our data indicate that cacna1aa loss-of-function zebrafish may be considered a new model of absence epilepsy and may prove useful both for the investigation of Cacna1a-mediated epileptogenesis and for in vivo drug screening.

• Stonyte, Vilte; Martîn, Ruth Martîn; Segura-Pena, Dario; Sekulic, Nikolina & Lopez Aviles, Sandra (2020). Requirement of PP2A-B56 Par1 for the Stabilization of the CDK Inhibitor Rum1 and Activation of APC/C Ste9 during Pre-Start G1 in S. pombe. iScience.  ISSN 2589-0042.  23(5) . doi: 10.1016/j.isci.2020.101063 Fulltekst i vitenarkiv. Vis sammendrag

  Exit from the cell cycle during the establishment of quiescence and upon cell differentiation requires the sustained inactivation of CDK complexes. Fission yeast cells deprived of nitrogen halt cell cycle progression in pre-Start G1, before becoming quiescent or undergoing sexual differentiation. The CDK inhibitor Rum1 and the APC/C activator Ste9 are fundamental for this arrest, but both are down-regulated by CDK complexes. Here, we show that PP2A-B56Par1 is instrumental for Rum1 stabilization and Ste9 activation. In the absence of PP2A-B56Par1, cells fail to accumulate Rum1, and this results in persistent CDK activity, Ste9 inactivation, retention of the mitotic cyclin Cdc13, and impaired withdrawal from the cell cycle during nitrogen starvation. Importantly, mutation of a putative B56 interacting motif in Rum1 recapitulates these defects. These results underscore the relevance of CDK-counteracting phosphatases in cell differentiation, establishment of the quiescent state, and escape from it in cancer cells.

• Hannula-Jouppi, Katariina; Harjama, Liisa; Einarsdottir, Elisabet; Elomaa, Outi; Kettunen, Kaisa; Saarela, Janna; Soronen, Minna; Bouchard, Laura; Lappalainen, Katriina; Heikkilä, Hannele; Kivirikko, Sirpa; Seppänen, Mikko R J; Kere, Juha & Ranki, Annamari (2020). Nagashima-type palmoplantar keratosis in Finland caused by a SERPINB7 founder mutation. Journal of American Academy of Dermatology.  ISSN 0190-9622.  83(2), s 643- 645 . doi: https://doi.org/10.1016/j.jaad.2019.11.004 Fulltekst i vitenarkiv.
• Harjama, Liisa; Kettunen, Kaisa; Elomaa, Outi; Einarsdottir, Elisabet; Heikkilä, Hannele; Kivirikko, Sirpa; Lappalainen, Katriina; Saarela, Janna; Alby, Caroline; Ranki, Annamari; Kere, Juha; Hadj-Rabia, Smaïl & Hannula-Jouppi, Katariina (2020). Phenotypic Variability with SLURP1 Mutations and Diffuse Palmoplantar Keratoderma. Acta Dermato-Venereologica.  ISSN 0001-5555.  100(4) . doi: https://doi.org/10.2340/00015555-3404 Fulltekst i vitenarkiv.
• Hakonen, Anna H; Lehtonen, Johanna; Kivirikko, Sirpa; Keski‐Filppula, Riikka; Moilanen, Jukka; Kivisaari, Reetta; Almusa, Henrikki; Jakkula, Eveliina; Saarela, Janna; Avela, Kristiina & Aittomäki, Kristiina (2020). Recessive MYH3 variants cause “Contractures, pterygia, and variable skeletal fusions syndrome 1B” mimicking Escobar variant multiple pterygium syndrome. American Journal of Medical Genetics. Part A.  ISSN 1552-4825.  182(11), s 2605- 2610 . doi: https://doi.org/10.1002/ajmg.a.61836 Vis sammendrag

  The multiple pterygium syndromes (MPS) are rare disorders with disease severity ranging from lethal to milder forms. The nonlethal Escobar variant MPS (EVMPS) is characterized by multiple pterygia and arthrogryposis, as well as various additional features including congenital anomalies. The genetic etiology of EVMPS is heterogeneous and the diagnosis has been based either on the detection of pathogenic CHRNG variants (~23% of patients), or suggestive clinical features. We describe four patients with a clinical suspicion of EVMPS who manifested with multiple pterygia, mild flexion contractures of several joints, and vertebral anomalies. We revealed recessively inherited MYH3 variants as the underlying cause in all patients: two novel variants, c.1053C>G, p.(Tyr351Ter) and c.3102+5G>C, as compound heterozygous with the hypomorphic MYH3 variant c.‐9+1G>A. Recessive MYH3 variants have been previously associated with spondylocarpotarsal synostosis syndrome. Our findings now highlight multiple pterygia as an important feature in patients with recessive MYH3 variants. Based on all patients with recessive MYH3 variants reported up to date, we consider that this disease entity should be designated as “Contractures, pterygia, and variable skeletal fusions syndrome 1B,” as recently suggested by OMIM. Our findings underline the importance of analyzing MYH3 in the differential diagnosis of EVMPS, particularly as the hypomorphic MYH3 variant might remain undetected by routine exome sequencing.

• Partanen, Terhi; Chen, Jie; Lehtonen, Johanna; Kuismin, Outi; Rusanen, Harri; Vapalahti, Olli; Vaheri, Antti; Anttila, Veli-Jukka; Bode, Michaela; Hautala, Nina; Vuorinen, Tytti; Glumoff, Virpi; Kraatari, Minna; Åström, Pirjo; Saarela, Janna; Kauma, Heikki; Lorenzo, Lazaro; Casanova, Jean-Laurent; Zhang, Shen-Ying; Seppänen, Mikko & Hautala, Timo (2020). Heterozygous TLR3 Mutation in Patients with Hantavirus Encephalitis. Journal of Clinical Immunology.  ISSN 0271-9142.  40(8) . doi: https://doi.org/10.1007/s10875-020-00834-2 Fulltekst i vitenarkiv. Vis sammendrag

  Puumala hantavirus (PUUV) hemorrhagic fever with renal syndrome (HFRS) is common in Northern Europe; this infection is usually self-limited and severe complications are uncommon. PUUV and other hantaviruses, however, can rarely cause encephalitis. The pathogenesis of these rare and severe events is unknown. In this study, we explored the possibility that genetic defects in innate anti-viral immunity, as analogous to Toll-like receptor 3 (TLR3) mutations seen in HSV-1 encephalitis, may explain PUUV encephalitis. We completed exome sequencing of seven adult patients with encephalitis or encephalomyelitis during acute PUUV infection. We found heterozygosity for the TLR3 p.L742F novel variant in two of the seven unrelated patients (29%, p = 0.0195). TLR3-deficient P2.1 fibrosarcoma cell line and SV40-immortalized fibroblasts (SV40-fibroblasts) from patient skin expressing mutant or wild-type TLR3 were tested functionally. The TLR3 p.L742F allele displayed low poly(I:C)-stimulated cytokine induction when expressed in P2.1 cells. SV40-fibroblasts from three healthy controls produced increasing levels of IFN-λ and IL-6 after 24 h of stimulation with increasing concentrations of poly(I:C), whereas the production of the cytokines was impaired in TLR3 L742F/WT patient SV40-fibroblasts. Heterozygous TLR3 mutation may underlie not only HSV-1 encephalitis but also PUUV hantavirus encephalitis. Such possibility should be further explored in encephalitis caused by these and other hantaviruses.

• Hautala, Timo; Chen, Jie; Tervonen, Laura; Partanen, Terhi; Winqvist, Satu; Lehtonen, Johanna; Saarela, Janna; Kraatari, Minna; Kuismin, Outi; Vuorinen, Tytti; Glumoff, Virpi; Åström, Pirjo; Huuskonen, Usko; Lorenzo, Lazaro; Casanova, Jean-Laurent; Zhang, Shen-Ying & Seppänen, Mikko R.J. (2020). Herpes simplex virus 2 encephalitis in a patient heterozygous for a TLR3 mutation. Neurology: Genetics.  ISSN 2376-7839.  6(6) . doi: https://doi.org/10.1212/NXG.0000000000000532 Fulltekst i vitenarkiv.
• Caglayan, Safak; Hashim, Adnan; Cieslar-Pobuda, Artur; Jensen, Vidar; Behringer, Sidney; Talug, Burcu; Chu, Dinh Toi; Pecquet, Christian; Rogne, Marie; Brech, Andreas; Brorson, Sverre Henning; Nagelhus, Erlend Arnulf; Hannibal, Luciana; Boschi, Antonella; Tasken, Kjetil & Staerk, Judith (2020). Optic Atrophy 1 Controls Human Neuronal Development by Preventing Aberrant Nuclear DNA Methylation. iScience.  ISSN 2589-0042.  23(6) . doi: 10.1016/j.isci.2020.101154 Fulltekst i vitenarkiv. Vis sammendrag

  Optic atrophy 1 (OPA1), a GTPase at the inner mitochondrial membrane involved in regulating mitochondrial fusion, stability, and energy output, is known to be crucial for neural development: Opa1 heterozygous mice show abnormal brain development, and inactivating mutations in OPA1 are linked to human neurological disorders. Here, we used genetically modified human embryonic and patient-derived induced pluripotent stem cells and reveal that OPA1 haploinsufficiency leads to aberrant nuclear DNA methylation and significantly alters the transcriptional circuitry in neural progenitor cells (NPCs). For instance, expression of the forkhead box G1 transcription factor, which is needed for GABAergic neuronal development, is repressed in OPA1+/− NPCs. Supporting this finding, OPA1+/− NPCs cannot give rise to GABAergic interneurons, whereas formation of glutamatergic neurons is not affected. Taken together, our data reveal that OPA1 controls nuclear DNA methylation and expression of key transcription factors needed for proper neural cell specification.

• Cieslar-Pobuda, Artur; Ahrens, Theresa Dorothee; Caglayan, Safak; Behringer, Sidney; Hannibal, Luciana & Staerk, Judith (2020). DNMT3B deficiency alters mitochondrial biogenesis and α‐ketoglutarate levels in human embryonic stem cells. Stem Cells.  ISSN 1066-5099.  38(11), s 1409- 1422 . doi: 10.1002/stem.3256 Fulltekst i vitenarkiv. Vis sammendrag

  Embryonic stem cell renewal and differentiation is regulated by metabolites that serve as cofactors for epigenetic enzymes. An increase of α‐ketoglutarate (α‐KG), a cofactor for histone and DNA demethylases, triggers multilineage differentiation in human embryonic stem cells (hESCs). To gain further insight into how the metabolic fluxes in pluripotent stem cells can be influenced by inactivating mutations in epigenetic enzymes, we generated hESCs deficient for de novo DNA methyltransferases (DNMTs) 3A and 3B. Our data reveal a bidirectional dependence between DNMT3B and α‐KG levels: a‐KG is significantly upregulated in cells deficient for DNMT3B, while DNMT3B expression is downregulated in hESCs treated with α‐KG. In addition, DNMT3B null hESCs exhibit a disturbed mitochondrial fission and fusion balance and a switch from glycolysis to oxidative phosphorylation. Taken together, our data reveal a novel link between DNMT3B and the metabolic flux of hESCs.

• Köksal, Elif; Liese, Susanne; Xue, Lin; Ryskulov, Ruslan; Viitala, Lauri; Carlson, Andreas & Gözen, Irep (2020). Rapid Growth and Fusion of Protocells in Surface‐Adhered Membrane Networks. Small.  ISSN 1613-6810.  16(38) . doi: 10.1002/smll.202002529 Vis sammendrag

  Elevated temperatures might have promoted the nucleation, growth, and replication of protocells on the early Earth. Recent reports have shown evidence that moderately high temperatures not only permit protocell assembly at the origin of life, but can have actively supported it. Here, the fast nucleation and growth of vesicular compartments from autonomously formed lipid networks on solid surfaces, induced by a moderate increase in temperature, are shown. Branches of the networks, initially consisting of self‐assembled interconnected nanotubes, rapidly swell into microcompartments which can spontaneously encapsulate RNA fragments. The increase in temperature further causes fusion of adjacent network‐connected compartments, resulting in the redistribution of the RNA. The experimental observations and the mathematical model indicate that the presence of nanotubular interconnections between protocells facilitates the fusion process.

• Gözen, Irep & Dommersnes, Paul Gunnar (2020). Biological lipid nanotubes and their potential role in evolution. The European Physical Journal Special Topics.  ISSN 1951-6355.  229(17-18), s 2843- 2862 . doi: 10.1140/epjst/e2020-000130-7 Fulltekst i vitenarkiv. Vis sammendrag

  The membrane of cells and organelles are highly deformable fluid interfaces, and can take on a multitude of shapes. One distinctive and particularly interesting property of biological membranes is their ability to from long and uniform nanotubes. These nanoconduits are surprisingly omnipresent in all domains of life, from archaea, bacteria, to plants and mammals. Some of these tubes have been known for a century, while others were only recently discovered. Their designations are different in different branches of biology, e.g. they are called stromule in plants and tunneling nanotubes in mammals. The mechanical transformation of flat membranes to tubes involves typically a combination of membrane anchoring and external forces, leading to a pulling action that results in very rapid membrane nanotube formation – micrometer long tubes can form in a matter of seconds. Their radius is set by a mechanical balance of tension and bending forces. There also exists a large class of membrane nanotubes that form due to curvature inducing molecules. It seems plausible that nanotube formation and functionality in plants and animals may have been inherited from their bacterial ancestors during endosymbiotic evolution. Here we attempt to connect observations of nanotubes in different branches of biology, and outline their similarities and differences with the aim of providing a perspective on their joint functions and evolutionary origin.

• Spustová, Karolina; Köksal, Elif; Ainla, Alar & Gözen, Irep (2020). Subcompartmentalization and Pseudo‐Division of Model Protocells. Small.  ISSN 1613-6810.  17(2) . doi: 10.1002/smll.202005320 Vis sammendrag

  Membrane enclosed intracellular compartments have been exclusively associated with the eukaryotes, represented by the highly compartmentalized last eukaryotic common ancestor. Recent evidence showing the presence of membranous compartments with specific functions in archaea and bacteria makes it conceivable that the last universal common ancestor and its hypothetical precursor, the protocell, may have exhibited compartmentalization. To the authors’ knowledge, there are no experimental studies yet that have tested this hypothesis. They report on an autonomous subcompartmentalization mechanism for protocells which results in the transformation of initial subcompartments to daughter protocells. The process is solely determined by the fundamental materials properties and interfacial events, and does not require biological machinery or chemical energy supply. In the light of the authors’ findings, it is proposed that similar events may have taken place under early Earth conditions, leading to the development of compartmentalized cells and potentially, primitive division.

• Guldvik, Ingrid Jenny; Zuber, Verena; Braadland, Peder Rustøen; Grytli, Helene Hartvedt; Ramberg, Håkon Andre; Lilleby, Wolfgang; Thiede, Bernd; Zucknick, Manuela; Saatcioglu, Fahri; Gislefoss, Randi Elin; Kvåle, Rune; George, Anne; Grönberg, Henrik; Wiklund, Fredrik; Neal, David E.; Gnanapragasam, Vincent J.; Tasken, Kristin Austlid & Mills, Ian Geoffrey (2020). Identification and Validation of Leucine-rich alpha-2-glycoprotein 1 as a Noninvasive Biomarker for Improved Precision in Prostate Cancer Risk Stratification.. European Urology Open Science.  ISSN 2666-1691.  21, s 51- 61 . doi: 10.1016/j.euros.2020.08.007 Fulltekst i vitenarkiv.
• Ali Ahmad, Ahmad & Sekulic, Nikolina (2020). CENP-A nucleosome-a chromatin-embedded pedestal for the centromere: lessons learned from structural biology. Essays in Biochemistry.  ISSN 0071-1365.  64(2), s 205- 221 . doi: 10.1042/EBC20190074 Fulltekst i vitenarkiv. Vis sammendrag

  The centromere is a chromosome locus that directs equal segregation of chromosomes during cell division. A nucleosome containing the histone H3 variant CENP-A epigenetically defines the centromere. Here, we summarize findings from recent structural biology studies, including several CryoEM structures, that contributed to elucidate specific features of the CENP-A nucleosome and molecular determinants of its interactions with CENP-C and CENP-N, the only two centromere proteins that directly bind to it. Based on those findings, we propose a role of the CENP-A nucleosome in the organization of centromeric chromatin beyond binding centromeric proteins.

• Tiraboschi, Ettore; Martina, Silvia; van der Ent, Wietske; Grzyb, Kamil; Gawel, Kinga Aurelia; Cordero-Maldonado, Maria Lorena; Poovathingal, Suresh K.; Heintz, Sarah; Somisetty, Venkata Satheesh; Brattespe, Jarle; Xu, Ju; Suster, Maximiliano; Skupin, Alexander & Esguerra, Camila (2020). New insights into the early mechanisms of epileptogenesis in a zebrafish model of Dravet syndrome. Epilepsia.  ISSN 0013-9580.  61(3), s 549- 560 . doi: 10.1111/epi.16456 Fulltekst i vitenarkiv. Vis sammendrag

  Abstract Objective: To pinpoint the earliest cellular defects underlying seizure onset (epileptogenic period) during perinatal brain development in a new zebrafish model of Dravet syndrome (DS) and to investigate potential disease-modifying activity of the 5HT2 receptor agonist fenfluramine. Methods: We used CRISPR/Cas9 mutagenesis to introduce a missense mutation, designed to perturb ion transport function in all channel isoforms, into scn1lab, the zebrafish orthologue of SCN1A (encoding voltage-gated sodium channel alpha subunit 1). We performed behavioral analysis and electroencephalographic recordings to measure convulsions and epileptiform discharges, followed by single-cell RNA-Seq, morphometric analysis of transgenic reporter-labeled γ-aminobutyric acidergic (GABAergic) neurons, and pharmacological profiling of mutant larvae. Results: Homozygous mutant (scn1labmut/mut ) larvae displayed spontaneous seizures with interictal, preictal, and ictal discharges (mean = 7.5 per 20-minute recording; P < .0001; one-way analysis of variance). Drop-Seq analysis revealed a 2:1 shift in the ratio of glutamatergic to GABAergic neurons in scn1labmut/mut larval brains versus wild type (WT), with dynamic changes in neuronal, glial, and progenitor cell populations. To explore disease pathophysiology further, we quantified dendritic arborization in GABAergic neurons and observed a 40% reduction in arbor number compared to WT (P < .001; n = 15 mutant, n = 16 WT). We postulate that the significant reduction in inhibitory arbors causes an inhibitory to excitatory neurotransmitter imbalance that contributes to seizures and enhanced electrical brain activity in scn1labmut/mut larvae (high-frequency range), with subsequent GABAergic neuronal loss and astrogliosis. Chronic fenfluramine administration completely restored dendritic arbor numbers to normal in scn1labmut/mut larvae, whereas similar treatment with the benzodiazepine diazepam attenuated seizures, but was ineffective in restoring neuronal cytoarchitecture. BrdU labeling revealed cell overproliferation in scn1labmut/mut larval brains that were rescued by fenfluramine but not diazepam. Significance: Our findings provide novel insights into early mechanisms of DS pathogenesis, describe dynamic cell population changes in the scn1labmut/mut brain, and present first-time evidence for potential disease modification by fenfluramine. Keywords: Dravet syndrome; epileptogenesis; fenfluramine; sodium channel; zebrafish.

• Khan, Aziz; Riudavets Puig, Rafael; Boddie, Paul & Mathelier, Anthony (2020). BiasAway: command-line and web server to generate nucleotide composition-matched DNA background sequences.. Bioinformatics.  ISSN 1367-4803. . doi: https://doi.org/10.1093/bioinformatics/btaa928 Fulltekst i vitenarkiv.
• Qiang, Jipeng; Ding, Wei; Kuijjer, Marieke Lydia; Quackenbush, John & Chen, Ping (2020). Clustering Sparse Data with Feature Correlation with Application to Discover Subtypes in Cancer. IEEE Access.  ISSN 2169-3536.  8, s 67775- 67789 Fulltekst i vitenarkiv.
• Andreeva, Olga; Li, Wei; Ding, Wei; Kuijjer, Marieke Lydia; Quackenbush, John & Chen, Ping (2020). Catalysis Clustering with GAN by Incorporating Domain Knowledge, In Rajesh Gupta & Yan Liu (ed.),  KDD '20: Proceedings of the 26th ACM SIGKDD International Conference on Knowledge Discovery & Data Mining.  Association for Computing Machinery (ACM).  ISBN 978-1-4503-7998-4.  Proceeding.  s 1344 - 1352
• Kuijjer, Marieke Lydia; Fagny, Maud; Marin, Alessandro; Quackenbush, John & Glass, Kimberly (2020). PUMA: PANDA Using MicroRNA Associations. Bioinformatics.  ISSN 1367-4803. . doi: 10.1093/bioinformatics/btaa571 Fulltekst i vitenarkiv.
• Kuijjer, Marieke Lydia (2020). Predicting Cancer Evolution Using Cell State Dynamics. Cancer Research.  ISSN 0008-5472.  80(15) . doi: 10.1158/0008-5472.CAN-20-1878
• Lopes-ramos, Camila; Chen, Cho-Yi; Kuijjer, Marieke Lydia; Paulson, Joseph N.; Sonawane, Abhijeet; Fagny, Maud; Platig, John; Glass, Kimberly; Quackenbush, John & DeMeo, Dawn L. (2020). Sex Differences in Gene Expression and Regulatory Networks across 29 Human Tissues. Cell reports.  ISSN 2211-1247.  31(12) . doi: 10.1016/j.celrep.2020.107795 Fulltekst i vitenarkiv.
• Weikum, Julia; Kulakova, Alina; Tesei, Giulio; Yoshimoto, Shogo; Vejby Jægerum, Line; Schütz, Monika; Hori, Katsutoshi; Skepö, Marie; Harris, Pernille; Leo, Jack Christopher & Morth, Jens Preben (2020). The extracellular juncture domains in the intimin passenger adopt a constitutively extended conformation inducing restraints to its sphere of action. Scientific Reports.  ISSN 2045-2322.  10(1) . doi: 10.1038/s41598-020-77706-7 Fulltekst i vitenarkiv.
• Perdreau-Dahl, Harmonie; Progida, Cinzia; Barfeld, Stefan Jörg; Guldsten, Hanne; Thiede, Bernd; Arntzen, Magnus Øverlie; Bakke, Oddmund; Mills, Ian Geoffrey; Krauss, Stefan & Morth, Jens Preben (2020). Sjögren syndrome/scleroderma autoantigen 1 is a direct Tankyrase binding partner in cancer cells. Communications Biology.  ISSN 2399-3642.  3(1) . doi: 10.1038/s42003-020-0851-2
• Põldsalu, Inga; Rohtlaid, Kätlin; Plesse, Cedric; Vidal, Frédéric; Nguyen, Ngoc Tuan; Peikolainen, Anna-Liisa; Tamm, Tarmo & Kiefer, Rudolf (2020). Printed PEDOT: PSS trilayer: Mechanism evaluation and application in energy storage. Materials.  ISSN 1996-1944.  13(2), s 1- 13 . doi: 10.3390/ma13020491 Fulltekst i vitenarkiv.
• Arain, Fizza Kanwal; Abraityte, Judita Aurelija; Bogdanova, Mariia; Solberg, Ole Geir; Michelsen, Annika; Lekva, Tove; Aakhus, Svend; Holm, Sverre; Halvorsen, Bente; Finsen, Alexandra; Vinge, Leif Erik; Nymo, Ståle Haugset; Espeland, Torvald; Ranheim, Trine; Aukrust, Pål; Vaage, Ingvar Jarle; Auensen, Andreas; Gullestad, Lars & Ueland, Thor (2020). YKL-40 (Chitinase-3-Like Protein 1) Serum Levels in Aortic Stenosis. Circulation: Heart Failure.  ISSN 1941-3289.  13(10), s e006643 . doi: 10.1161/CIRCHEARTFAILURE.119.006643 Fulltekst i vitenarkiv.
• Tuovinen, Elina A.; Grönholm, Juha; Ohman, Tiina; Pöysti, Sakari; Toivonen, Raine; Kreutzman, Anna; Heiskanen, Kaarina; Trotta, Luca; Toiviainen-Salo, Sanna; Routes, John M.; Verbsky, James; Mustjoki, Satu; Saarela, Janna; Kere, Juha; Varjosalo, Markku; Hänninen, Arno & Seppänen, Mikko (2020). Novel Hemizygous IL2RG p.(Pro58Ser) Mutation Impairs IL-2 Receptor Complex Expression on Lymphocytes Causing X-Linked Combined Immunodeficiency. Journal of Clinical Immunology.  ISSN 0271-9142.  40(3), s 503- 514 . doi: 10.1007/s10875-020-00745-2 Fulltekst i vitenarkiv.
• Gawel, Kinga Aurelia; Kukula-Koch, Wirginia; Nieoczym, Dorota; Stępnik, Katarzyna; van der Ent, Wietske; Banono, Nancy Saana; Tarabasz, Dominik; Turski, Waldemar A. & Esguerra, Camila (2020). The Influence of Palmatine Isolated from Berberis sibirica Radix on Pentylenetetrazole-Induced Seizures in Zebrafish. Cells.  ISSN 2073-4409.  9(5) . doi: 10.3390/cells9051233 Fulltekst i vitenarkiv. Vis sammendrag

  Palmatine (PALM) and berberine (BERB) are widely identified isoquinoline alkaloids among the representatives of the Berberidaceae botanical family. The antiseizure activity of BERB was shown previously in experimental epilepsy models. We assessed the effect of PALM in a pentylenetetrazole (PTZ)-induced seizure assay in zebrafish, with BERB as an active reference compound. Both alkaloids were isolated from the methanolic root extract of Berberis sibirica by counter-current chromatography, and their ability to cross the blood-brain barrier was determined via quantitative structure-activity relationship assay. PALM exerted antiseizure activity, as confirmed by electroencephalographic analysis, and decreased c-fos and bdnf levels in PTZ-treated larvae. In a behavioral assay, PALM dose-dependently decreased PTZ-induced hyperlocomotion. The combination of PALM and BERB in ED16 doses revealed hyperadditive activity towards PTZ-induced hyperlocomotion. Notably, we have indicated that both alkaloids may exert their anticonvulsant activity through different mechanisms of action. Additionally, the combination of both alkaloids in a 1:2.17 ratio (PALM: BERB) mimicked the activity of the pure extract, which indicates that these two active compounds are responsible for its anticonvulsive activity. In conclusion, our study reveals for the first time the anticonvulsant activity of PALM and suggests the combination of PALM and BERB may have higher therapeutic value than separate usage of these compounds.

• Banono, Nancy Saana; Gawel, Kinga Aurelia; De Witte, Linus & Esguerra, Camila (2020). Zebrafish Larvae Carrying a Splice Variant Mutation in cacna1d: A New Model for Schizophrenia-Like Behaviours?. Molecular Neurobiology.  ISSN 0893-7648.  58, s 877- 894 . doi: 10.1007/s12035-020-02160-5 Fulltekst i vitenarkiv. Vis sammendrag

  Persons with certain single nucleotide polymorphisms (SNPs) in the CACNA1D gene (encoding voltage-gated calcium channel subunit alpha 1-D) have increased risk of developing neuropsychiatric disorders such as bipolar, schizophrenia and autism. The molecular consequences of SNPs on gene expression and protein function are not well understood. Thus, the use of animal models to determine genotype-phenotype correlations is critical to understanding disease pathogenesis. Here, we describe the behavioural changes in larval zebrafish carrying an essential splice site mutation (sa17298) in cacna1da. Heterozygous mutation resulted in 50% reduction of splice variants 201 and 202 (haploinsufficiency), while homozygosity increased transcript levels of variant 201 above wild type (WT; gain-of-function, GOF). Due to low homozygote viability, we focused primarily on performing the phenotypic analysis on heterozygotes. Indeed, cacna1dasa17298/WT larvae displayed hyperlocomotion—a behaviour characterised in zebrafish as a surrogate phenotype for epilepsy, anxiety or psychosis-like behaviour. Follow-up tests ruled out anxiety or seizures, however, as neither thigmotaxis defects nor epileptiform-like discharges in larval brains were observed. We therefore focused on testing for potential “psychosis-like” behaviour by assaying cacna1dasa17298/WT larval locomotor activity under constant light, during light-dark transition and in startle response to dark flashes. Furthermore, exposure of larvae to the antipsychotics, risperidone and haloperidol reversed cacna1da-induced hyperactivity to WT levels while valproate decreased but did not reverse hyperactivity. Together, these findings demonstrate that cacna1da haploinsufficiency induces behaviours in larval zebrafish analogous to those observed in rodent models of psychosis. Future studies on homozygous mutants will determine how cacna1d GOF alters behaviour in this context.

• Mahmutovic, Anel; Abel zur Wiesch, Pia & Abel, Sören (2020). Selection or drift: the population biology underlying transposon insertion sequencing experiments.. Computational and Structural Biotechnology Journal.  ISSN 2001-0370.  18, s 791- 804 . doi: 10.1016/j.csbj.2020.03.021 Fulltekst i vitenarkiv.
• Clarelli, Fabrizio; Palmer, Adam; Singh, Bhupender; Storflor, Merete; Lauksund, Silje; Cohen, Ted; Abel, Sören & Abel zur Wiesch, Pia (2020). Drug-target binding quantitatively predicts optimal antibiotic dose levels in quinolones. PLoS Computational Biology.  ISSN 1553-734X. . doi: 10.1371/journal.pcbi.1008106 Fulltekst i vitenarkiv.
• Barkovskaya, Anna; Seip, Kotryna; Prasmickaite, Lina; Mills, Ian Geoffrey; Moestue, Siver Andreas & Itkonen, Harri (2020). Inhibition of O-GlcNAc transferase activates tumor-suppressor gene expression in tamoxifen-resistant breast cancer cells. Scientific Reports.  ISSN 2045-2322.  10, s 1- 10 . doi: 10.1038/s41598-020-74083-z Fulltekst i vitenarkiv.
• Villatoro, Alicia; Konieczny, Joanna; Cuminetti, Vincent & Arranz, Lorena (2020). Leukemia Stem Cell Release From the Stem Cell Niche to Treat Acute Myeloid Leukemia. Frontiers in Cell and Developmental Biology.  ISSN 2296-634X.  8, s 607 . doi: 10.3389/fcell.2020.00607 Fulltekst i vitenarkiv.
• Mohammadzadeh, Naiyereh; Melleby, Arne Olav; Palmero, Sheryl; Sjaastad, Ivar; Chakravarti, Shukti; Engebretsen, Kristin V Thunheim; Christensen, Geir Arve; Lunde, Ida Gjervold & Tønnessen, Theis (2020). Moderate Loss of the Extracellular Matrix Proteoglycan Lumican Attenuates Cardiac Fibrosis in Mice Subjected to Pressure Overload. Cardiology.  ISSN 0008-6312.  145(3), s 187- 198 . doi: 10.1159/000505318
• Pladsen, Arne Valebjørg; Nilsen, Gro; Rueda, Oscar M.; Aure, Miriam Ragle; Borgan, Ørnulf; Liestøl, Knut; Vitelli, Valeria; Frigessi Di Rattalma, Arnoldo; Langerød, Anita; Mathelier, Anthony; Engebråten, Olav; Kristensen, Vessela N.; Wedge, David C.; Van Loo, Peter; Caldas, Carlos; Børresen-Dale, Anne-Lise; Russnes, Hege Elisabeth Giercksky & Lingjærde, Ole Christian (2020). DNA copy number motifs are strong and independent predictors of survival in breast cancer. Communications Biology.  ISSN 2399-3642.  3 . doi: 10.1038/s42003-020-0884-6 Fulltekst i vitenarkiv.
• Gawel, Kinga Aurelia; Langlois, Melanie; Martins, Teresa G.; van der Ent, Wietske; Tiraboschi, Ettore; Jacmin, Maxime; Crawford, Alexander Dettmar & Esguerra, Camila V. (2020). Seizing the moment: Zebrafish epilepsy models. Neuroscience and Biobehavioral Reviews.  ISSN 0149-7634.  116, s 1- 20 . doi: 10.1016/j.neubiorev.2020.06.010 Fulltekst i vitenarkiv.
• Banono, Nancy Saana & Esguerra, Camila (2020). Pharmacological validation of the prepulse inhibition of startle response in larval zebrafish using a commercial automated system and software. Journal of Visualized Experiments.  ISSN 1940-087X.  161 . doi: 10.3791/61423 Fulltekst i vitenarkiv. Vis sammendrag

  Tamoxifen is the most prescribed selective estrogen receptor (ER) modulator in patients with ER-positive breast cancers. Tamoxifen requires the transcription factor paired box 2 protein (PAX2) to repress the transcription of ERBB2/HER2. Now, we identified that PAX2 inhibits cell growth of ER+/HER2− tumor cells in a dose-dependent manner. Moreover, we have identified that cell growth inhibition can be achieved by expressing moderate levels of PAX2 in combination with tamoxifen treatment. Global run-on sequencing of cells overexpressing PAX2, when coupled with PAX2 ChIP-seq, identified common targets regulated by both PAX2 and tamoxifen. The data revealed that PAX2 can inhibit estrogen-induced gene transcription and this effect is enhanced by tamoxifen, suggesting that they converge on repression of the same targets. Moreover, PAX2 and tamoxifen have an additive effect and both induce coding genes and enhancer RNAs (eRNAs). PAX2–tamoxifen upregulated genes are also enriched with PAX2 eRNAs. The enrichment of eRNAs is associated with the highest expression of genes that positivity regulate apoptotic processes. In luminal tumors, the expression of a subset of these proapoptotic genes predicts good outcome and their expression are significantly reduced in tumors of patients with relapse to tamoxifen treatment. Mechanistically, PAX2 and tamoxifen coexert an antitumoral effect by maintaining high levels of transcription of tumor suppressors that promote cell death. The apoptotic effect is mediated in large part by the gene interferon regulatory factor 1. Altogether, we conclude that PAX2 contributes to better clinical outcome in tamoxifen treated ER-positive breast cancer patients by repressing estrogen signaling and inducing cell death related pathways.

• Ramonet Jimenez, Jose David & Dietz, Gunnar P.H. (2020). Novel cell-based assay for identification of LRRK2 inhibitors using its aberrant regulation of a pluripotency gene. SLAS Discovery.  ISSN 2472-5552.  25(1), s 104- 112 . doi: 10.1177/2472555219864086
• Khalid, Khalisanni; Tan, Xuefei; Mohd Zaid, Hayyiratul Fatimah; Tao, Yang; Lye Chew, Chien; Chu, Dinh Toi; Lam, Man Kee; Ho, Yeek-Chia; Lim, Jun Wei & Chin Wei, Lai (2020). Advanced in developmental organic and inorganic nanomaterial: a review. Bioengineered.  ISSN 2165-5979.  11(1), s 328- 355 . doi: 10.1080/21655979.2020.1736240 Fulltekst i vitenarkiv. Vis sammendrag

  With the unique properties such as high surface area to volume ratio, stability, inertness, ease of functionalization, as well as novel optical, electrical, and magnetic behaviors, nanomaterials have a wide range of applications in various fields with the common types including nanotubes, dendrimers, quantum dots, and fullerenes. With the aim of providing useful insights to help future development of efficient and commercially viable technology for large-scale production, this review focused on the science and applications of inorganic and organic nanomaterials, emphasizing on their synthesis, processing, characterization, and applications on different fields. The applications of nanomaterials on imaging, cell and gene delivery, biosensor, cancer treatment, therapy, and others were discussed in depth. Last but not least, the future prospects and challenges in nanoscience and nanotechnology were also explored.

• Chu, Dinh Toi; Phuong, Thuy Nguyen Thi; Tien, Nguyen Le Bao; Tran, Dang Khoa; Thanh, Vo Van; Quang, Thuy Luu; Truong, Dang Tien; Pham, Van-Huy; Ngoc, Vo Truong Nhu; Chu-Dinh, Thien & Kushekhar, Kushi (2020). An update on the progress of isolation, culture, storage, and clinical application of human bone marrow mesenchymal stem/stromal cells. International Journal of Molecular Sciences.  ISSN 1422-0067.  21:708(3), s 1- 27 . doi: 10.3390/ijms21030708 Fulltekst i vitenarkiv.
• Lindner, Paula Maria; Christensen, Søren Brøgger; Nissen, Poul; Møller, Jesper Vuust & Engedal, Nikolai (2020). Cell death induced by the ER stressor thapsigargin involves death receptor 5, a non-autophagic function of MAP1LC3B, and distinct contributions from unfolded protein response components. Cell Communication and Signaling.  ISSN 1478-811X.  18(1), s 1- 23 . doi: 10.1186/s12964-019-0499-z Fulltekst i vitenarkiv.
• Martîn, Ruth Martîn; Stonyte, Vilte & Lopez Aviles, Sandra (2020). Protein phosphatases in G1 regulation. International Journal of Molecular Sciences.  ISSN 1422-0067.  21:395(2), s 1- 15 . doi: 10.3390/ijms21020395 Fulltekst i vitenarkiv. Vis sammendrag

  Eukaryotic cells make the decision to proliferate, to differentiate or to cease dividing during G1, before passage through the restriction point or Start. Keeping cyclin-dependent kinase (CDK) activity low during this period restricts commitment to a new cell cycle and is essential to provide the adequate timeframe for the sensing of environmental signals. Here, we review the role of protein phosphatases in the modulation of CDK activity and as the counteracting force for CDK-dependent substrate phosphorylation, in budding and fission yeast. Moreover, we discuss recent findings that place protein phosphatases in the interface between nutritional signalling pathways and the cell cycle machinery.

• Meås, Hany Zakaria; Haug, Markus; Beckwith, Marianne Sandvold; Louet, Claire; Ryan, Liv; Hu, Zhenyi; Landskron, Johannes; Nordbø, Svein Arne; Tasken, Kjetil; Yin, Hang; Damås, Jan Kristian & Flo, Trude Helen (2020). Sensing of HIV-1 by TLR8 activates human T cells and reverses latency. Nature Communications.  ISSN 2041-1723.  11:147, s 1- 16 . doi: 10.1038/s41467-019-13837-4 Fulltekst i vitenarkiv. Vis sammendrag

  During HIV infection, cell-to-cell transmission results in endosomal uptake of the virus by target CD4+ T cells and potential exposure of the viral ssRNA genome to endosomal Toll-like receptors (TLRs). TLRs are instrumental in activating inflammatory responses in innate immune cells, but their function in adaptive immune cells is less well understood. Here we show that synthetic ligands of TLR8 boosted T cell receptor signaling, resulting in increased cytokine production and upregulation of surface activation markers. Adjuvant TLR8 stimulation, but not TLR7 or TLR9, further promoted T helper cell differentiation towards Th1 and Th17. In addition, we found that endosomal HIV induced cytokine secretion from CD4+ T cells in a TLR8-specific manner. TLR8 engagement also enhanced HIV-1 replication and potentiated the reversal of latency in patient-derived T cells. The adjuvant TLR8 activity in T cells can contribute to viral dissemination in the lymph node and low-grade inflammation in HIV patients. In addition, it can potentially be exploited for therapeutic targeting and vaccine development.

• Fan, Qiong; Nørgaard, Rikke Christine; Grytten, Ivar; Ness, Cecilie Maria; Lucas, Christin; Vekterud, Kristin; Soedling, Helen; Matthews, Jason; Lemma, Roza Berhanu; Gabrielsen, Odd Stokke; Bindesbøll, Christian; Ulven, Stine Marie; Nebb, Hilde Irene; Grønning-Wang, Line Mariann & Sæther, Thomas (2019). Open the LID: LXRα regulates ChREBPα transactivity in a target gene-specific manner through an agonist-modulated LBD-LID interaction. BioRxiv.  ISSN 0362-4331. . doi: 10.1101/2019.12.20.869974 Vis sammendrag

  The cholesterol-sensing nuclear receptor liver X receptor (LXR) and the glucose-sensing transcription factor carbohydrate responsive element-binding protein (ChREBP) are central players in regulating glucose and lipid metabolism in liver. We have previously shown that LXR regulates ChREBP transcription and activity; however, the underlying mechanisms are unclear. In the current study, we demonstrate that LXRα and ChREBPα interact physically, and show a high co-occupancy at regulatory regions in the mouse genome. LXRα co-activates ChREBPα, and regulates ChREBP-specific target genes in vitro and in vivo. This co-activation is dependent on functional recognition elements for ChREBP, but not for LXR, indicating that ChREBPα recruits LXRα to chromatin in trans. The two factors interact via their key activation domains; ChREBPα’s low glucose inhibitory domain (LID) and the ligand-binding domain (LBD) of LXRα. While unliganded LXRα co-activates ChREBPα, ligand-bound LXRα surprisingly represses ChREBPα activity on ChREBP-specific target genes. Mechanistically, this is due to a destabilized LXRα:ChREBPα interaction, leading to reduced ChREBP-binding to chromatin and restricted activation of glycolytic and lipogenic target genes. This ligand-driven molecular switch highlights an unappreciated role of LXRα that was overlooked due to LXR lipogenesis-promoting function.

• Connell, Shea P; Yazbek-Hanna, Marcelino; McCarthy, Frank; Hurst, Rachel; Webb, Martyn; Curley, Helen; Walker, Helen; Mills, Rob; Ball, Richard Y; Sanda, Martin G.; Pellegrini, Kathryn L; Patil, Dattatraya; Perry, Antoinette; Schalken, Jack A.; Pandha, Hardev; Whitaker, Hayley; Dennis, Nening; Stuttle, Christine; Mills, Ian Geoffrey; Guldvik, Ingrid Jenny; Parker, Chris; Brewer, Daniel; Cooper, Colin S. & Clark, Jeremy P. (2019). A four‐group urine risk classifier for predicting outcomes in patients with prostate cancer. BJU International.  ISSN 1464-4096.  124(4), s 609- 620 . doi: 10.1111/bju.14811 Fulltekst i vitenarkiv.
• Keskitalo, Salla; Haapaniemi, Emma M.; Glumoff, Virpi; Liu, Xiaonan; Lehtinen, Ville; Fogarty, Christopher; Rajala, Hanna; Chiang, Samuel C.; Mustjoki, Satu; Kovanen, Panu; Lohi, Jouko; Bryceson, Yenan; Seppänen, Mikko; Kere, Juha; Heiskanen, Kaarina & Varjosalo, Markku (2019). Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease. NPJ GENOMIC MEDICINE.  ISSN 2056-7944.  4:14, s 1- 7 . doi: 10.1038/s41525-019-0088-5 Fulltekst i vitenarkiv.
• Joemetsa, Silver; Spustová, Karolina; Kustanovich, Kiryl; Ainla, Alar; Schindler, Severin; Eigler, Siegfried; Lobovkina, Tatsiana; Lara-Avila, Samuel; Jesorka, Aldo & Gözen, Irep (2019). Molecular Lipid Films on Microengineering Materials. Langmuir.  ISSN 0743-7463.  35(32), s 10286- 10298 . doi: 10.1021/acs.langmuir.9b01120
• Kustanovich, Kiryl; Yantchev, Ventsislav; Doosti, Baharan Ali; Gözen, Irep & Jesorka, Aldo (2019). A microfluidics-integrated impedance/surface acoustic resonance tandem sensor. Sensing and Bio-Sensing Research.  25 . doi: 10.1016/j.sbsr.2019.100291
• Vo, Truong Nhu Ngoc; Chu, Dinh Toi; Duong, Duc Long; Bui, Van Nhon; Tong, Minh Son; Nguyen, Thi Thu Phuong; Le, Quynh-Anh; Nguyen, Khanh-Hoang; Pham, Van-Huy & Chu-Dinh, Thien (2019). Efficacy of electrochemically activated water solution in gingivitis treatment. Journal of Pharmaceutical Investigation (JPI).  ISSN 2093-5552.  49(3), s 323- 329 . doi: 10.1007/s40005-018-00419-7
• Truong-Nhu-Ngoc, Vo; Vu-Thai-Lien, Nguyen; Minh-Hang, Luong; Thanh-Tung, Doan; Thi-Nga, Vu; Pham-The, Hai & Chu, Dinh Toi (2019). Radicular cyst in a primary molar following pulp therapy with gutta percha: A case report and literature review. Journal of Clinical and Experimental Dentistry.  11(1), s e85- e90 . doi: 10.4317/jced.55309
• Gawel, Kinga Aurelia; Turski, Waldemar A.; van der Ent, Wietske; Mathai, Benan John; Kirstein-Smardzewska, Karolina Joanna; Simonsen, Anne & Esguerra, Camila V. (2019). Phenotypic Characterization of Larval Zebrafish (Danio rerio) with Partial Knockdown of the cacna1a Gene. Molecular Neurobiology.  ISSN 0893-7648. . doi: 10.1007/s12035-019-01860-x Fulltekst i vitenarkiv.
• Kamiński, Krzysztof; Socała, Katarzyna; Zagaja, Mirosław; Andres-Mach, Marta; Abram, Michał; Jakubiec, Marcin; Pieróg, Mateusz; Nieoczym, Dorota; Rapacz, Anna; Esguerra, Camila V.; Gawel, Kinga Aurelia; Latacz, Gniewomir; Lubelska, Annamaria; Szulczyk, Bartłomiej; Szewczyk, Aleksandra; Łuszczki, Jarogniew Jacek & Wlaź, Piotr (2019). N-Benzyl-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) with Hybrid Structure as a Candidate for a Broad-Spectrum Antiepileptic Drug. Neurotherapeutics.  ISSN 1933-7213. . doi: 10.1007/s13311-019-00773-w Fulltekst i vitenarkiv.
• Fromm, Bastian; Domanska, Diana Ewa; Høye, Eirik; Ovchinnikov, Vladimir; Kang, Wenjing; Aparicio-Puerta, Ernesto; Johansen, Morten; Flatmark, Kjersti; Mathelier, Anthony; Hovig, Eivind; Hackenberg, Michael; Friedländer, Marc R. & Peterson, Kevin J. (2019). MirGeneDB 2.0: the metazoan microRNA complement. Nucleic Acids Research (NAR).  ISSN 0305-1048.  48(D1), s D132- D141 . doi: 10.1093/nar/gkz885 Fulltekst i vitenarkiv.
• Skånland, Sigrid Strand & Cieslar-Pobuda, Artur (2019). Off-label uses of drugs for depression. European Journal of Pharmacology.  ISSN 0014-2999.  865 . doi: 10.1016/j.ejphar.2019.172732 Fulltekst i vitenarkiv.
• Salvatore, Stefania; Rand, Knut Dagestad; Grytten, Ivar; Ferkingstad, Egil; Domanska, Diana; Holden, Lars; Gheorghe, Marius; Mathelier, Anthony; Glad, Ingrid Kristine & Sandve, Geir Kjetil (2019). Beware the Jaccard: the choice of similarity measure is important and non-trivial in genomic colocalisation analysis. Briefings in Bioinformatics.  ISSN 1467-5463.  s 1- 8 . doi: 10.1093/bib/bbz083
• Barnett, Ian; Nishant, Malik; Kuijjer, Marieke Lydia; Mucha, Peter & Onnela, Jukka-Pekka (2019). Feature-based classification of networks. Network Science.  ISSN 2050-1242.  7(3), s 438- 444 . doi: https://doi.org/10.1017/nws.2019.21
• Fagny, Maud; Platig, John; Kuijjer, Marieke Lydia; Lin, Xihong & Quackenbush, John (2019). Nongenic cancer-risk SNPs affect oncogenes, tumour-suppressor genes, and immune function. British Journal of Cancer.  ISSN 0007-0920. . doi: 10.1038/s41416-019-0614-3 Fulltekst i vitenarkiv.
• Kuijjer, Marieke Lydia; Hsieh, Ping-Han; Quackenbush, John & Glass, Kimberly (2019). lionessR: single sample network inference in R. BMC Cancer.  ISSN 1471-2407.  19(1003) . doi: 10.1186/s12885-019-6235-7 Fulltekst i vitenarkiv.
• Kuijjer, Marieke Lydia; Tung, Matthew George; Yuan, GuoCheng; Quackenbush, John & Glass, Kimberly (2019). Estimating Sample-Specific Regulatory Networks. iScience.  ISSN 2589-0042.  14, s 226- 240 . doi: 10.1016/j.isci.2019.03.021 Fulltekst i vitenarkiv.
• Wong, Kim; van der Weyden, Louise; Schott, Courtney R.; Foote, Alastair; Constantino-Casas, Fernando; Smith, Sionagh; Dobson, Jane M.; Murchison, Elizabeth P.; Wu, Hong; Yeh, Iwei; Fullen, Douglas R.; Joseph, Nancy; Bastian, Boris C.; Patel, Rajiv M.; Martincorena, Inigo; Robles-Espinoza, Carla Daniela; Iyer, Vivek; Kuijjer, Marieke Lydia; Arends, Mark J.; Brenn, Thomas; Harms, Paul W.; Wood, Geoffrey A. & Adams, David J. (2019). Cross-species genomic landscape comparison of human mucosal melanoma with canine oral and equine melanoma. Nature Communications.  ISSN 2041-1723.  10(353), s 1- 14 . doi: 10.1038/s41467-018-08081-1 Fulltekst i vitenarkiv.
• Zhen, Yan; Spangenberg, Helene; Munson, Michael Joseph; Brech, Andreas; Schink, Kay Oliver; Tan, Kia Wee; Sørensen, Vigdis; Wenzel, Eva; Radulovic, Maja; Engedal, Nikolai; Simonsen, Anne; Raiborg, Camilla & Stenmark, Harald (2019). ESCRT-mediated phagophore sealing during mitophagy. Autophagy.  ISSN 1554-8627.  s 1- 16 . doi: 10.1080/15548627.2019.1639301 Fulltekst i vitenarkiv.
• Handle, Florian; Prekovic, Stefan; Helsen, Christine; van den Broeck, Thomas; Smeets, Elien; Moris, Lisa; Eerlings, Roy; El Kharraz, Sarah; Urbanucci, Alfonso; Mills, Ian Geoffrey; Joniau, Steven; Attard, Gerhardt & Claessens, Frank (2019). Drivers of AR indifferent anti-androgen resistance in prostate cancer cells. Scientific Reports.  ISSN 2045-2322.  9(13786), s 1- 11 . doi: 10.1038/s41598-019-50220-1 Fulltekst i vitenarkiv.
• Ha, Thomas J.; Zhang, Peter G.Y.; Robert, Remi; Yeung, Joanna; Swanson, Douglas J.; Mathelier, Anthony; Wasserman, Wyeth W.; Im, Sujin; Itoh, Masayoshi; Kawaji, Hideya; Lassmann, Timo; Daub, Carsten O.; Arner, Erik; Carninci, Piero; Hayashizaki, Yoshihide; Forrest, Alistair R.R. & Goldowitz, Daniel (2019). Identification of novel cerebellar developmental transcriptional regulators with motif activity analysis. BMC Genomics.  ISSN 1471-2164.  20(718), s 1- 17 . doi: 10.1186/s12864-019-6063-9 Fulltekst i vitenarkiv.
• Vu, Le Nguyen; Nghia, Nguyen Quang; Thanh, Do Truong; Giang, Tran Binh; Nga, Vu Thi; Bui, Le Minh & Chu, Dinh Toi (2019). Laparoscopic living donor right nephrectomy: Assessment of outcome and association of BMI to length of right renal vein. Actas Urológicas Españolas.  ISSN 0210-4806.  43(10), s 536- 542 . doi: 10.1016/j.acuro.2019.05.005
• Behringer, Sidney; Wingert, Victoria; Oria, Victor; Schumann, Anke; Grünert, Sarah; Cieslar-Pobuda, Artur; Kölker, Stefan; Lederer, Ann-Kathrin; Jacobsen, Donald W.; Stärk, Judith; Schilling, Oliver; Spiekerkoetter, Ute & Hannibal, Luciana (2019). Targeted metabolic profiling of methionine cycle metabolites and redox thiol pools in mammalian plasma, cells and urine. Metabolites.  ISSN 2218-1989.  9:235(10), s 1- 27 . doi: 10.3390/metabo9100235 Fulltekst i vitenarkiv.
• Copmans, Daniëlle; Kildgaard, Sara; Rasmussen, Silas A.; Ślęzak, Monika; Dirkx, Nina; Partoens, Michèle; Esguerra, Camila Vicencio; Crawford, Alexander Dettmar; Larsen, Thomas O. & de Witte, Peter A.M. (2019). Zebrafish-based discovery of antiseizure compounds from the north sea: Isoquinoline alkaloids TMC-120A and TMC-120B. Marine Drugs.  ISSN 1660-3397.  17:607(11), s 1- 20 . doi: 10.3390/md17110607 Fulltekst i vitenarkiv.
• Nielsen, Nis Valentin; Roedel, Elfie; Manna, Dipankar; Etscheid, Michael; Morth, Jens Preben & Kanse, Sandip (2019). Characterization of the enzymatic activity of the serine protease domain of Factor VII activating protease (FSAP). Scientific Reports.  ISSN 2045-2322.  9(1) . doi: 10.1038/s41598-019-55531-x Fulltekst i vitenarkiv.
• Braadland, Peder Rustøen; Ramberg, Håkon Andre; Grytli, Helene Hartvedt; Urbanucci, Alfonso; Nielsen, Heidi Kristin; Guldvik, Ingrid Jenny; Engedahl, Andreas; Ketola, Kirsi; Wanzhong, Wang; Svindland, Aud; Mills, Ian Geoffrey; Bjartell, Anders & Tasken, Kristin Austlid (2019). The β2-adrenergic receptor is a molecular switch for neuroendocrine transdifferentiation of prostate cancer cells. Molecular Cancer Research.  ISSN 1541-7786.  17(11), s 2154- 2168 . doi: 10.1158/1541-7786.MCR-18-0605
• Tepekule, Burcu; Abel zur Wiesch, Pia; Kouyos, Roger D. & Bonhoeffer, Sebastian (2019). Quantifying the impact of treatment history on plasmid-mediated resistance evolution in human gut microbiota. Proceedings of the National Academy of Sciences of the United States of America.  ISSN 0027-8424.  116(46), s 23106- 23116 . doi: 10.1073/pnas.1912188116 Fulltekst i vitenarkiv.
• Skånland, Sigrid Strand; Cremaschi, Andrea; Bendiksen, Henrik; Hermansen, Johanne Uthus; Thimiri Govinda Raj, Deepak Balaji; Munthe, Ludvig Andre; Tjønnfjord, Geir Erland & Tasken, Kjetil (2019). An in vitro assay for biomarker discovery and dose prediction applied to ibrutinib plus venetoclax treatment of CLL. Leukemia.  ISSN 0887-6924. . doi: 10.1038/s41375-019-0569-7
• Korecki, Andrea J; Hickmott, Jack W; Lam, Siu Ling; Dreolini, Lisa; Mathelier, Anthony; Baker, Oliver; Kuehne, Claudia; Bonaguro, Russell J; Smith, Jillian; Tan, Chin-Vern; Zhou, Michelle; Goldowitz, Daniel; Deussing, Jan M; Stewart, A. Francis; Wasserman, Wyeth W.; Holt, Robert A & Simpson, Elizabeth M (2019). Twenty-seven tamoxifen-inducible icre-driver mouse strains for eye and brain, including seventeen carrying a new inducible-first constitutive-ready allele. Genetics.  ISSN 0016-6731.  211(4), s 1155- 1177 . doi: 10.1534/genetics.119.301984
• Halnes, Geir; Pettersen, Klas Henning; Øyehaug, Leiv; Rognes, Marie Elisabeth & Einevoll, Gaute (2019). Astrocytic Ion Dynamics: Implications for Potassium Buffering and Liquid Flow, In Hugues Berry & Maurizio De Pittà (ed.),  Computational Glioscience.  Springer Nature.  ISBN 978-3-030-00817-8.  Chapter.  s 363 - 391
• Mayer, Alexander E.; Löffler, Mona C; Valdés, Angel E Loza; Schmitz, Werner; El-Merahbi, Rabih; Viera, Jonathan Trujillo; Erk, Manuela; Zhang, Tianzhou; Braun, Ursula Barbara; Heikenwalder, Mathias; Leitges, Michael; Schulze, Almut & Sumara, Grzegorz (2019). The kinase PKD3 provides negative feedback on cholesterol and triglyceride synthesis by suppressing insulin signaling. Science Signaling.  ISSN 1945-0877.  12(593) . doi: 10.1126/scisignal.aav9150
• Sisodiya, Sanjay M.; Fowler, Hayley J.; Lake, Iain; Nanji, Rosemary Ogwen; Gawel, Kinga Aurelia; Esguerra, Camila Vicencio; Newton, Charles & Foley, Aideen (2019). Climate change and epilepsy: Time to take action. Epilepsia Open.  ISSN 2470-9239.  4(4), s 524- 536 . doi: 10.1002/epi4.12359 Fulltekst i vitenarkiv.

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• Sekulic, Nikolina; Cascella, Michele & Hovet, Oda (2020). Molecular Dynamics Studies on the Essential Mitotic Protein Kinase – Aurora B.
• Song, You; Hultman, Maria Thérése; Moe, Jannicke; Petersen, Karina; Rundberget, Jan Thomas; Xie, Li; Cao, Yang; Esguerra, Camila Vicencio; De Bin, Riccardo; Lee, YeonKyeong; Solhaug, Knut Asbjørn; Kamstra, Jorke H; Legler, Juliette; Iguchi, Taisen; Lillicrap, Adam David; Andersen, Sjur; Villeneuve, Daniel L. & Tollefsen, Knut-Erik (2020). The RiskAOP project - Quantitative Adverse Outcome Pathway assisted risk assessment of mitochondrial toxicants.
• Banono, Nancy Saana (2020). Investigating the functional effects of single nucleotide variants (SNVs) in schizophrenia risk genes: using the zebrafish as the model organism.
• Kuijjer, Marieke Lydia; Paulson, Joseph N. & Quackenbush, John (2020). Expression analysis, In Andreas D. Baxevanis; Gary D. Bader & David S. Wishart (ed.),  Bioinformatics.  John Wiley & Sons.  ISBN 978-1-119-33558-0.  Chapter 10.  s 279 - 314
• Kersten, Flore Marie C & Heim, Joel Benjamin (2020). Structural characterization of urea channels and their role in infectious diseases.
• Heim, Joel Benjamin (2020). Inhibitor development for Mpro, the main protease of SARS-CoV-2.
• Heim, Joel Benjamin; Kersten, Flore Marie Colette; Cunha, Eva & Luecke, Hartmut (2020). Survival in acidic environments – Structure and mechanism of bacterial urea channels.
• Banono, Nancy Saana; Gawel, Kinga Aurelia; De Witte, Linus & Esguerra, Camila (2020). Zebrafish larvae carrying a mutation in cacna1d display schizophrenia-like behaviours.
• Bengtsen, Mads; Winje, Ivan; Landskron, Johannes; Meza-Zepeda, Leonardi A & Gundersen, Kristian (2019). The Epigenetic landscape of two phenotypic extreme skeletal muscles.
• Bengtsen, Mads; Winje, Ivan; Landskron, Johannes; Meza-Zepeda, Leonardo A. & Gundersen, Kristian (2019). The Epigenetic landscape of two phenotypic extreme skeletal muscles.
• Bengtsen, Mads; Winje, Ivan; Eftestøl, Einar; Domanska, Diana Ewa; Landskron, Johannes & Gundersen, Kristian (2019). The Epigenetic landscape of two phenotypic extreme skeletal muscles - soleus and EDL. Acta Physiologica.  ISSN 1748-1708. . doi: 10.1111/apha.13414
• Sharapova, Svetlana O.; Haapaniemi, Emma; Sakovich, Inga S.; Kostyuchenko, Larysa V.; Donkó, Agnes; Dulau-Florea, Alina; Malko, Oksana; Bondarenko, Anastasia V.; Stegantseva, Maria V.; Leto, Thomas L.; Uygun, Vedat; Karasu, Gülsün Tezcan; Holland, Steven M.; Hsu, Amy P. & Aleinikova, Olga V. (2019). Heterozygous activating mutation in RAC2 causes infantile-onset combined immunodeficiency with susceptibility to viral infections. Clinical Immunology.  ISSN 1521-6616.  205, s 1- 5 . doi: 10.1016/j.clim.2019.05.003
• Lopes-ramos, Camila; Kuijjer, Marieke Lydia; Ogino, Shuji; Fuchs, Charles S.; DeMeo, Dawn L.; Glass, Kimberly & Quackenbush, John (2019). Correction: Gene Regulatory Network Analysis Identifies Sex-Linked Differences in Colon Cancer Drug Metabolism. Cancer Research.  ISSN 0008-5472.
• Meås, Hany Zakaria; Haug, Markus; Beckwith, Marianne Sandvold; Louet, Claire; Ryan, Liv; Hu, Z.; Landskron, Johannes; Nordbø, Svein Arne; Tasken, Kjetil; Yin, H. H.; Damås, Jan Kristian & Flo, Trude Helen (2019). Sensing of HIV-1 by TLR8 activates human T cells and reverses latency.
• Haug, Markus; Meås, Hany Zakaria; Beckwith, Marianne Sandvold; Louet, Claire; Ryan, Liv; Hu, Z.; Landskron, Johannes; Nordbø, Svein Arne; Tasken, Kjetil; Yin, H. H.; Damås, Jan Kristian & Flo, Trude Helen (2019). Sensing of HIV-1 by TLR8 in human CD4+ T cells. Vis sammendrag

  Cell-to-cell transmission of HIV can result in endosomal uptake of HIV by CD4+ T cells with possible exposure of viral ssRNA genome to endolysosomal Toll-like receptors (TLRs). TLRs are central in activating inflammatory responses in innate immune cells, but their function in CD4+ T cells is less well understood. Here we show that combined TLR8 ligand and T cell receptor (TCR) stimulation boosted CD4+ T cell activation by enhancing NF-B and MAPK signaling. This led to increased production of inflammatory cytokines and surface activation marker expression. Adjuvant TLR8 stimulation, but not TLR7 or TLR9, promoted interleukin (IL)-17 and interferon (IFN)- effector cytokine production, indicating lineage commitment towards the pro-inflammatory T helper (Th)1 and Th17 axis. Using a cell-to-cell transmission model, we found that endosomal HIV induced cytokine secretion from CD4+ T cells, which could be significantly reduced by a TLR8 specific inhibitor. TLR8 engagement also enhanced HIV replication in CD4+ T cells and potentiated the reversal of latency in patient-derived CD4+ T cells. Taken together, our results reveal a previously unknown function of TLR8 in human primary CD4+ T cells in shaping immunity and modulating HIV-1 infection. This adjuvant TLR8 activity can contribute to low-grade inflammation seen in HIV patients and may also have implications for therapeutic targeting and vaccine development.

• Haug, Markus; Meås, Hany Zakaria; Beckwith, Marianne Sandvold; Louet, Claire; Ryan, Liv; Hu, Z.; Landskron, Johannes; Nordbø, Svein Arne; Tasken, Kjetil; Yin, H. H.; Damås, Jan Kristian & Flo, Trude Helen (2019). Sensing of HIV-1 nucleic acids by TLR8 in human CD4+ T cells. Vis sammendrag

  During HIV-infection, cell-to-cell transmission results in endosomal uptake of the virus by target CD4+ T cells and potential exposure of the viral ssRNA genome to endolysosomal Toll-like receptors (TLRs). TLRs are instrumental in activating inflammatory responses in innate immune cells, but their function in adaptive immune cells is less well understood. Here we show that combined TLR8 ligand and T cell receptor (TCR) stimulation boosted CD4+ T cell activation by enhancing NF-kB and MAPK signaling. This led to increased production of inflammatory cytokines and surface activation marker expression. Adjuvant TLR8 stimulation, but not TLR7 or TLR9, promoted interleukin (IL)-17 and interferon (IFN)-g effector cytokine production, indicating lineage commitment towards the pro-inflammatory T helper (Th)1 and Th17 axis. Using a cell-to-cell transmission model, we found that endosomal HIV-1 induced cytokine secretion from CD4+ T cells, which could be significantly reduced by a TLR8 specific inhibitor. TLR8 engagement also enhanced HIV-1 replication in CD4+ T cells and potentiated the reversal of latency in patient-derived CD4+ T cells. Taken together, our results reveal a previously unknown function of TLR8 in human primary CD4+ T cells in shaping immunity and modulating HIV-1 infection. This adjuvant TLR8 activity can contribute to low-grade inflammation seen in HIV patients and may have broad implications for therapeutic targeting and vaccine development.

• Fan, Qiong; Nørgaard, Rikke Christine; Grytten, Ivar; Ness, Cecilie Maria; Lucas, Christin; Vekterud, Kristin; Södling, Helen; Matthews, Jason; Lemma, Roza Berhanu; Gabrielsen, Odd Stokke; Bindesbøll, Christian; Ulven, Stine Marie; Nebb, Hilde Irene; Grønning-Wang, Line Mariann & Sæther, Thomas (2019). LXRα interacts with the glucose-sensing transcription factor ChREBPα to regulate its transcriptional activity.. Vis sammendrag

  The cholesterol-sensing nuclear receptor Liver X Receptor (LXR) and the glucose-sensing transcription factor carbohydrate responsive element-binding protein (ChREBP) are central players in the regulation of glucose and lipid metabolism. LXR does this job in part by regulating the expression of ChREBP. We have previously shown that LXR also regulates ChREBP activity. To get a better understanding of mechanisms at play, we asked if LXR and ChREBP interact physically. Interestingly, LXRα binds to ChREBPα, but not the shorter isoform ChREBPβ. Co-immunoprecipitation (CoIP) of different LXR and ChRBEP domains shows that it is ChREBPα’s low glucose inhibitory domain (LID), which is lacking in ChREBPβ, that interacts with the ligand-binding domain (LBD) of LXRα. In line with this, we see a surprisingly high co-occupancy of LXR and ChREBP on regulatory regions in the mouse genome when re-analysing two independently published chromatin immunoprecipitation-sequencing (ChIP-seq) datasets. Moreover, Functional studies show that LXRα is able to co-activate together with ChREBPα, but not ChREBPβ, and increase ChREBP-specific target gene expression in vitro and in vivo. Unexpectedly however, ligand-engaged LXR exhibits a repressive effect on the expression of the same genes in primary mouse hepatocytes, in contrast to what we observe with target genes that are common to LXR and ChREBP. Performing CoIP and ChIP on selected target genes, we demonstrate mechanistically that the repressive effect most likely is due to a weakened ChREBPα:LXRα interaction and reduced binding of ChREBP to chromatin. Altogether, the novel transcriptional complex comprising ChREBPα and LXRα adds to the intricate integration of nutrient signals in glucose and lipid metabolism.

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