Torunn Rønningen

• Svensson, Stina Ingrid Alice; Saeed, Sadia; Hoffmann, Anne; Ghosh, Adhideb; Wolfrum, Christian & Dahl, Mai Britt [Vis alle 15 forfattere av denne artikkelen] (2025). HOOK1 Gene Expression and DNA Methylation in Obesity and Related Cardiometabolic Traits. Obesity Facts. ISSN 1662-4025. doi: 10.1159/000547603. Fulltekst i vitenarkiv Vis sammendrag

  Introduction: Accumulation of fat in omental visceral adipose tissue (OVAT) is strongly linked to metabolic diseases. Our recent findings show a distinct and more accessible chromatin landscape of the visceral depot compared to its subcutaneous counterpart. Based on integrated analysis of chromatin accessibility and transcriptomics, we identified previously unrecognised genes linked with obesity. Here, we performed in-depth analyses of one of the candidates, HOOK1, and tested for depot-specific gene expression, correlation with clinical traits and regulatory mechanisms including DNA methylation. Methods: We utilised intra-individually paired adipose tissue samples of human OVAT and subcutaneous adipose tissue (SAT) from our in-house cohort (N = 78). Gene expression was measured using real-time quantitative PCR and pyrosequencing was used to determine DNA methylation levels. Data were analysed for differential gene expression and DNA methylation differences between SAT and OVAT, along with correlation analyses with clinical variables related to obesity. Results were validated in adipose tissue samples from 1,618 donors of the Leipzig Obesity Biobank. Results: We observed consistently higher HOOK1 gene expression in OVAT compared to SAT and successfully confirmed this effect direction in several validation cohorts. We further identified that HOOK1 gene expression correlated with body mass index and hip circumference. We discovered a relationship between DNA methylation of the HOOK1 promoter with clinical variables important for liver function. Conclusion: Our data show that HOOK1 gene expression is adipose tissue depot-specific. We observed that gene expression and DNA methylation are correlated to clinical variables of obesity, suggesting that HOOK1 may play a role in obesity and its sequelae.

• Rønningen, Torunn; Zeng, Yong; Dahl, Mai Britt; Wang, Junbai; Visnovska, Martina & Tannæs, Tone Møller [Vis alle 18 forfattere av denne artikkelen] (2025). Global mapping of RNA N6-methyladenosine (m6A) in human subcutaneous and visceral adipose tissue reveals novel targets that correlate with clinical variables of obesity. Biomarker Research. 13(1). doi: 10.1186/s40364-025-00857-0. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Background Obesity is a major health challenge and fat accumulation in visceral depots is more strongly associated with metabolic comorbidities than deposition in subcutaneous depots. Epitranscriptomic regulation of gene expression by N 6 -methyladenosine (m 6 A) influences various aspects of RNA metabolism, however the m 6 A methylome in human adipose tissue and its relationship with fat distribution has not yet been investigated in detail. Methods In this study, we performed epitranscriptomic mapping of m 6 A in intra-individually paired samples of subcutaneous (SAT) and omental visceral adipose tissue (OVAT) from women with normal weight (BMI ≤25, n  = 3) and obesity (BMI ≥35, n  = 10) using meRIP-seq (discovery cohort). We further investigated differential m 6 A methylation for specific target genes in a larger cohort of individuals with obesity ( n  = 72, validation cohort) using meRIP-qPCR. meRIP-seq was performed for primary adipocytes from a subset of the patients ( n  = 4) to account for cell type specific differences. Results We here provide the first global map of m 6 A in human adipose tissue in paired samples of SAT and OVAT. We show an overall high overlap in m 6 A sites between individuals and depots, but also distinct depot-specific differences. We identify 339 target genes showing depot-specific m 6 A methylation. Depot-specific methylation was validated for selected sites in SEMA3A , SNAP47 and PPP1R9A in a larger validation cohort. We additionally identify differentially methylated targets between lean individuals and individuals with obesity, including TSC22D1 , FMNL2 and IL1R1 . By combining data from primary adipocytes with data from corresponding bulk adipose tissue, we identified a higher number of genes containing m 6 A in non-adipocyte cells in OVAT compared to SAT. Mechanistically, we show for selected targets that m 6 A affects RNA lifetime in pre-adipocyte cell culture models. Importantly, m 6 A methylation in selected targets correlates with clinically important variables related to obesity, fat distribution and glucose metabolism. Conclusions We identify a catalogue of novel targets showing adipose tissue depot specific m 6 A methylation, with potential as biomarkers in metabolic disease. Our findings underscore the regulatory role of m 6 A in obesity and provide valuable insights for future research. The datasets generated represent a significant resource for further insight in adipose tissue biology and its implications for metabolic health.

• Saeed, Sadia; Poulsen, Lars La Cour; Visnovska, Martina; Hoffmann, Anne; Ghosh, Adhideb & Wolfrum, Christian [Vis alle 18 forfattere av denne artikkelen] (2025). Chromatin landscape in paired human visceral and subcutaneous adipose tissue and its impact on clinical variables in obesity. EBioMedicine. 114. doi: 10.1016/j.ebiom.2025.105653. Fulltekst i vitenarkiv Vis sammendrag

  Background Obesity is a global health challenge and adipose tissue exhibits distinct depot-specific characteristics impacting differentially on the risk of metabolic comorbidities. Methods Here, we integrate chromatin accessibility (ATAC-seq) and gene expression (RNA-seq) data from intra-individually paired human subcutaneous (SAT) and omental visceral adipose tissue (OVAT) samples to unveil depot-specific regulatory mechanisms. Findings We identified twice as many depot-specific differentially accessible regions (DARs) in OVAT compared to SAT. SAT-specific regions showed enrichment for adipose tissue enhancers involving genes controlling extracellular matrix organization and metabolic processes. In contrast, OVAT-specific regions showed enrichment in promoters linked to genes associated with cardiomyopathies. Moreover, OVAT-specific regions were enriched for bivalent transcription start site and repressive chromatin states, suggesting a “lingering” regulatory state. Motif analysis identified CTCF and BACH1 as most significantly enriched motifs in SAT and OVAT-specific DARs, respectively. Distinct gene sets correlated with important clinical variables of obesity, fat distribution measures, as well as insulin, glucose, and lipid metabolism. Interpretation We provide an integrated analysis of chromatin accessibility and transcriptional profiles in paired human SAT and OVAT samples, offering new insights into the regulatory landscape of adipose tissue and highlighting depot-specific mechanisms in obesity pathogenesis.

• Rønningen, Torunn; Dahl, Mai Britt; Valderhaug, Tone Gretland; Cayir, Akin; Keller, Maria & Tönjes, Anke [Vis alle 8 forfattere av denne artikkelen] (2021). m6A Regulators in Human Adipose Tissue - Depot-Specificity and Correlation With Obesity. Frontiers in Endocrinology. 12. doi: 10.3389/fendo.2021.778875. Fulltekst i vitenarkiv Vis sammendrag

  Background: N6-methyladenosine (m6A) is one of the most abundant post-transcriptional modifications on mRNA influencing mRNA metabolism. There is emerging evidence for its implication in metabolic disease. No comprehensive analyses on gene expression of m6A regulators in human adipose tissue, especially in paired adipose tissue depots, and its correlation with clinical variables were reported so far. We hypothesized that inter-depot specific gene expression of m6A regulators may differentially correlate with clinical variables related to obesity and fat distribution. Methods: We extracted intra-individually paired gene expression data (omental visceral adipose tissue (OVAT) N=48; subcutaneous adipose tissue (SAT) N=56) of m6A regulators from an existing microarray dataset. We also measured gene expression in another sample set of paired OVAT and SAT (N=46) using RT-qPCR. Finally, we extracted existing gene expression data from peripheral mononuclear blood cells (PBMCs) and single nucleotide polymorphisms (SNPs) in METTL3 and YTHDF3 from genome wide data from the Sorbs population (N=1049). The data were analysed for differential gene expression between OVAT and SAT; and for association with obesity and clinical variables. We further tested for association of SNP markers with gene expression and clinical traits. Results: In adipose tissue we observed that several m6A regulators (WTAP, VIRMA, YTHDC1 and ALKBH5) correlate with obesity and clinical variables. Moreover, we found adipose tissue depot specific gene expression for METTL3, WTAP, VIRMA, FTO and YTHDC1. In PBMCs, we identified ALKBH5 and YTHDF3 correlated with obesity. Genetic markers in METTL3 associate with BMI whilst SNPs in YTHDF3 are associated with its gene expression. Conclusions: Our data show that expression of m6A regulators correlates with obesity, is adipose tissue depot-specific and related to clinical traits. Genetic variation in m6A regulators adds an additional layer of variability to the functional consequences.

• Rohde, Kerstin; Rønningen, Torunn; Poulsen, Lars La Cour; Keller, Maria; Blüher, Matthias & Böttcher, Yvonne (2020). Role of the DNA repair genes H2AX and HMGB1 in human fat distribution and lipid profiles. BMJ Open Diabetes Research & Care. 8(1), s. 1–7. doi: 10.1136/bmjdrc-2019-000831. Fulltekst i vitenarkiv Vis sammendrag

  Introduction Regional fat distribution strongly relates to metabolic comorbidities. We identified the DNA repair genes H2AX and HMGB1 to be differentially expressed between human subcutaneous (SAT) and omental visceral adipose tissue (OVAT) depots. As increased DNA damage is linked to metabolic disease, we here sought to analyze whether depot-specific H2AX and HMGB1 expression is related to anthropometric and metabolic profiles of obesity. We further tested for different H2AX mRNA regulatory mechanisms by analyzing promoter DNA methylation and genotyped rs7350 in the H2AX locus. Research design and methods Gene expression (OVAT n=48; SAT n=55) and DNA promoter methylation data (OVAT and SAT n=77) were extracted from an existing dataset as described elsewhere. Genotype data for the 3’untranslated region (3’UTR) H2AX variant rs7350 were generated by using the TaqMan genotyping system in 243 subjects of the same cohort. Statistical analyses were done using SPSS statistics software 24 and GraphPad Prism 6. Results We identified H2AX being higher (p=0.002) and HMGB1 being less expressed (p=0.0001) in OVAT compared with SAT. Further, we observed positive interdepot correlations of OVAT and SAT for both HMGB1 (p=1×10 –6 ) and H2AX mRNA levels (p=0.024). Depot-specific associations were observed for both genes’ methylation levels with either high density lipoprotein cholesterol, low density lipoprotein cholesterol, triglycerides and/or with OVAT/SAT-ratio (all p<0.05). A significantly lower level of total cholesterol in minor A-Allele carriers of rs7350 compared with AG and GG carriers (p=0.001) was observed. Additionally, subjects carrying the A-allele showed lower SAT HMGB1 expression level (p=0.030). Conclusion Our results suggest a fat depot-specific regulation of H2AX and HMGB1 potentially mediated by both DNA methylation and genetic variation. Rs7350, DNA methylation and/or mRNA levels of H2AX and HMGB1 are related to lipid parameters. Further studies are warranted to evaluate the functional role of the DNA repair genes H2AX and HMGB1 in obesity and fat distribution.

• Rohde, Kerstin; Keller, Maria; Poulsen, Lars La Cour; Rønningen, Torunn; Stumvoll, Michael & Tonjes, Anke [Vis alle 11 forfattere av denne artikkelen] (2019). (Epi)genetic regulation of CRTC1 in human eating behaviour and fat distribution. EBioMedicine. 44, s. 476–488. doi: 10.1016/j.ebiom.2019.05.050. Fulltekst i vitenarkiv Vis sammendrag

  Background In brain, CREB-regulated transcription co-activator 1 (CRTC1) is involved in metabolic dysregulation. In humans a SNP in CRTC1 was associated to body fat percentage and two SNPs affected RNA Pol II binding and chromatin structure, implying epigenetic regulation of CRTC1. We sought to understand the relevance of CRTC1 SNPs, DNA methylation and expression in human eating behaviour and its relationship to clinical variables of obesity in blood and adipose tissue. Methods 13 CRTC1 SNPs were included to analyze eating behaviour. For rs7256986, follow up association analyses were applied on DNA methylation, CRTC1 expression and clinical parameters. Linear regression was used throughout the study adjusted for age, sex and BMI. Besides data extraction from previous work, rs7256986 was de-novo genotyped and DNA methylation was evaluated by using pyrosequencing. Findings We found several SNPs in the CRTC1 locus nominally associated with human eating behaviour or 2hr postprandial insulin levels and observed a correlation with alcohol and coffee intake (all P < 0.05). G-allele carriers of rs7256986 showed slightly increased hip circumference. We showed that rs7256986 represents a methylation quantitative trait locus (meQTL) in whole blood and adipose tissue. The presence of the SNP and/or DNA methylation correlated with CRTC1 gene expression which in turn, related to BMI and fat distribution. Interpretation Our data support the known role of CRCT1 regulating energy metabolism in brain. Here, we highlight relevance of CRTC1 regulation in blood and adipose tissue. Fund IFB AdiposityDiseases (BMBF); n609020-Scientia Fellows; Helse-SørØst; DFG: CRC 1052/1 and/2; Kompetenznetz Adipositas, German Diabetes Association.

• Briand, Nolwenn; Cahyani, Inswasti; Madsen-Østerbye, Julia-Kristina Jensen; Paulsen, Jonas; Rønningen, Torunn & Sørensen, Anita Løvstad [Vis alle 7 forfattere av denne artikkelen] (2018). Lamin A, Chromatin and FPLD2:Not ust a Peripheral Ménage-à-Trois. Frontiers in Cell and Developmental Biology. 6. doi: 10.3389/fcell.2018.00073. Fulltekst i vitenarkiv Vis sammendrag

  At the nuclear periphery, the genome is anchored to A- and B-type nuclear lamins in the form of heterochromatic lamina-associated domains. A-type lamins also associate with chromatin in the nuclear interior, away from the peripheral nuclear lamina. This nucleoplasmic lamin A environment tends to be euchromatic, suggesting distinct roles of lamin A in the regulation of gene expression in peripheral and more central regions of the nucleus. The hot-spot lamin A R482W mutation causing familial partial lipodystrophy of Dunnigan-type (FPLD2), affects lamin A association with chromatin at the nuclear periphery and in the nuclear interior, and is associated with 3-dimensional (3D) rearrangements of chromatin. Here, we highlight features of nuclear lamin association with the genome at the nuclear periphery and in the nuclear interior. We address recent data showing a rewiring of such interactions in cells from FPLD2 patients, and in adipose progenitor and induced pluripotent stem cell models of FPLD2. We discuss associated epigenetic and genome conformation changes elicited by the lamin A R482W mutation at the gene level. The findings argue that the mutation adversely impacts both global and local genome architecture throughout the nucleus space. The results, together with emerging new computational modeling tools, mark the start of a new era in our understanding of the 3D genomics of laminopathies.

• Soop, Graciela Lopez; Rønningen, Torunn; Rogala, Agnieszka; Richartz, Nina; Blomhoff, Heidi Kiil & Thiede, Bernd [Vis alle 8 forfattere av denne artikkelen] (2017). AKAP95 interacts with nucleoporin TPR in mitosis and is important for the spindle assembly checkpoint. Cell Cycle. ISSN 1538-4101. 16(10), s. 947–956. doi: 10.1080/15384101.2017.1310350. Fulltekst i vitenarkiv Vis sammendrag

  Faithful chromosome segregation during mitosis relies on a proofreading mechanism that monitors proper kinetochore-microtubule attachments. The spindle assembly checkpoint (SAC) is based on the concerted action of numerous components that maintain a repressive signal inhibiting transition into anaphase until all chromosomes are attached. Here we show that A-Kinase Anchoring Protein 95 (AKAP95) is necessary for proper SAC function. AKAP95-depleted HeLa cells show micronuclei formed from lagging chromosomes at mitosis. Using a BioID proximity-based proteomic screen, we identify the nuclear pore complex protein TPR as a novel AKAP95 binding partner. We show interaction between AKAP95 and TPR in mitosis, and an AKAP95-dependent enrichment of TPR in the spindle microtubule area in metaphase, then later in the spindle midzone area. AKAP95-depleted cells display faster prometaphase to anaphase transition, escape from nocodazole-induced mitotic arrest and show a partial delocalization from kinetochores of the SAC component MAD1. Our results demonstrate an involvement of AKAP95 in proper SAC function likely through its interaction with TPR.

• Rønningen, Torunn; Shah, Akshay; Oldenburg, Anja; Vekterud, Kristin; Delbarre, Erwan & Moskaug, Jan Øivind [Vis alle 7 forfattere av denne artikkelen] (2015). Prepatterning of differentiation-driven nuclear lamin A/C-associated chromatin domains by GlcNAcylated histone H2B. Genome Research. ISSN 1088-9051. 25(12), s. 1825–1835. doi: 10.1101/gr.193748.115. Fulltekst i vitenarkiv Vis sammendrag

  Dynamic interactions of nuclear lamins with chromatin through lamin-associated domains (LADs) contribute to spatial arrangement of the genome. Here, we provide evidence for prepatterning of differentiation-driven formation of lamin A/C LADs by domains of histone H2B modified on serine 112 by the nutrient sensor O-linked N-acetylglucosamine (H2BS112GlcNAc), which we term GADs. We demonstrate a two-step process of lamin A/C LAD formation during in vitro adipogenesis, involving spreading of lamin A/C–chromatin interactions in the transition from progenitor cell proliferation to cell-cycle arrest, and genome-scale redistribution of these interactions through a process of LAD exchange within hours of adipogenic induction. Lamin A/C LADs are found both in active and repressive chromatin contexts that can be influenced by cell differentiation status. De novo formation of adipogenic lamin A/C LADs occurs nonrandomly on GADs, which consist of megabase-size intergenic and repressive chromatin domains. Accordingly, whereas predifferentiation lamin A/C LADs are gene-rich, post-differentiation LADs harbor repressive features reminiscent of lamin B1 LADs. Release of lamin A/C from genes directly involved in glycolysis concurs with their transcriptional up-regulation after adipogenic induction, and with downstream elevations in H2BS112GlcNAc levels and O-GlcNAc cycling. Our results unveil an epigenetic prepatterning of adipogenic LADs by GADs, suggesting a coupling of developmentally regulated lamin A/C-genome interactions to a metabolically sensitive chromatin modification.

• Rønningen, Torunn; Shah, Akshay; Reiner, Andrew Henry; Collas, Philippe & Moskaug, Jan Øivind (2015). Epigenetic priming of inflammatory response genes by high glucose in adipose progenitor cells. Biochemical and Biophysical Research Communications - BBRC. ISSN 0006-291X. 467(4), s. 979–986. doi: 10.1016/j.bbrc.2015.10.030. Fulltekst i vitenarkiv Vis sammendrag

  Cellular metabolism confers wide-spread epigenetic modifications required for regulation of transcriptional networks that determine cellular states. Mesenchymal stromal cells are responsive to metabolic cues including circulating glucose levels and modulate inflammatory responses. We show here that long term exposure of undifferentiated human adipose tissue stromal cells (ASCs) to high glucose upregulates a subset of inflammation response (IR) genes and alters their promoter histone methylation patterns in a manner consistent with transcriptional de-repression. Modeling of chromatin states from combinations of histone modifications in nearly 500 IR genes unveil three overarching chromatin configurations reflecting repressive, active, and potentially active states in promoter and enhancer elements. Accordingly, we show that adipogenic differentiation in high glucose predominantly upregulates IR genes. Our results indicate that elevated extracellular glucose levels sensitize in ASCs an IR gene expression program which is exacerbated during adipocyte differentiation. We propose that high glucose exposure conveys an epigenetic ‘priming’ of IR genes, favoring a transcriptional inflammatory response upon adipogenic stimulation. Chromatin alterations at IR genes by high glucose exposure may play a role in the etiology of metabolic diseases.

• Preda, Mihai Bogdan; Rønningen, Torunn; Burlacu, Alexandrina; Simionescu, Maya; Moskaug, Jan Øivind & Valen, Guro (2014). Remote transplantation of mesenchymal stem cells protects the heart against ischemia-reperfusion injury. Stem Cells. ISSN 1066-5099. 32(8), s. 2123–2134. doi: 10.1002/stem.1687. Fulltekst i vitenarkiv

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• López-Soop, Graciela; Rønningen, Torunn; Rogala, Agnieszka; Richartz, Nina; Blomhoff, Heidi Kiil & Thiede, Bernd [Vis alle 8 forfattere av denne artikkelen] (2017). AKAP95 interacts with nucleoporin TPR in mitosis and is important for the spindle assembly checkpoint. Cell Cycle. ISSN 1538-4101. 16(10), s. 947–956. doi: 10.1080/15384101.2017.1310350. Fulltekst i vitenarkiv

Se alle arbeider i NVA