Kristin Vekterud

• Fan, Qiong; Nørgaard, Rikke Christine; Grytten, Ivar; Ness, Cecilie; 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 (2020). LXRα Regulates ChREBPα Transactivity in a Target Gene-Specific Manner through an Agonist-Modulated LBD-LID Interaction. Cells.  ISSN 2073-4409.  9(5), s 1- 26 . doi: 10.3390/cells9051214 Fulltekst i vitenarkiv. 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 the liver. More knowledge of their mechanistic interplay is needed to understand their role in pathological conditions like fatty liver disease and insulin resistance. In the current study, LXR and ChREBP co-occupancy was examined by analyzing ChIP-seq datasets from mice livers. LXR and ChREBP interaction was determined by Co-immunoprecipitation (CoIP) and their transactivity was assessed by real-time quantitative polymerase chain reaction (qPCR) of target genes and gene reporter assays. Chromatin binding capacity was determined by ChIP-qPCR assays. Our data show 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; the low glucose inhibitory domain (LID) of ChREBPα 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 in responding to nutritional cues that was overlooked due to LXR lipogenesis-promoting function.

• 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.

• Delbarre, Erwan; Ivanauskiene, Kristina; Spirkoski, Jane; Shah, Akshay; Vekterud, Kristin; Moskaug, Jan Øivind; Bøe, Stig Ove; Wong, Lee H.; Küntziger, Thomas M. & Collas, Philippe (2017). PML protein organizes heterochromatin domains where it regulates histone H3.3 deposition by ATRX/DAXX. Genome Research.  ISSN 1088-9051.  27(6), s 913- 921 . doi: 10.1101/gr.215830.116 Fulltekst i vitenarkiv.
• Rønningen, Torunn; Shah, Akshay; Oldenburg, Anja; Vekterud, Kristin; Delbarre, Erwan; Moskaug, Jan Øivind & Collas, Philippe (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
• Sørensen, Anita Løvstad; Barrand, Sanna Kristiina; West, Franklin D.; Vekterud, Kristin; Boquest, Andrew Craig; Åhrlund-Richter, Lars; Stice, Steve L. & Collas, Philippe (2010). Lineage-Specific Promoter DNA Methylation Patterns Segregate Adult Progenitor Cell Types. Stem Cells and Development.  ISSN 1547-3287.  19(8), s 1257- 1266 . doi: 10.1089/scd.2009.0309
• Frøystad-Saugen, Marianne K.; Lilleeng, Einar; Bakke-McKellep, Anne Marie; Vekterud, Kristin; Valen, Elin C.; Hemre, Gro-Ingunn & Krogdahl, Åshild (2009). Distal intestinal gene expression in Atlantic salmon (Salmo salar L.) fed genetically modified maize. Aquaculture Nutrition.  ISSN 1353-5773.  15(1), s 104- 115 . doi: 10.1111/j.1365-2095.2008.00572.x
• Frøystad, Marianne K.; Lilleeng, Einar; Bakke-McKellep, Anne Marie; Vekterud, Kristin; Hemre, Gro-Ingunn & Krogdahl, Åshild (2008). Gene expression in distal intestine of Atlantic salmon (Salmo salar L.) fed genetically modified soybean meal. Aquaculture Nutrition.  ISSN 1353-5773.  14(3), s 204- 214 . doi: 10.1111/j.1365-2095.2007.00519.x
• Boquest, Andrew Craig; Noer, Agate; Sørensen, Anita Løvstad; Vekterud, Kristin & Collas, Philippe (2007). CpG methylation profiles of endothelial cell-specific gene promoter regions in adipose tissue stem cells suggest limited differentiation potential toward the endothelial cell lineage. Stem Cells.  ISSN 1066-5099.  25(4), s 852- 861
• Lilleeng, Einar; Frøystad, Marianne K.; Vekterud, Kristin & Krogdahl, Åshild (2007). Comparison of intestinal gene expression in Atlantic cod (Gadus morhua) fed standard fish meal or soybean meal by means of suppression subtractive hybridization and real-time PCR. Aquaculture.  ISSN 0044-8486.  267(1-4), s 269- 283 Vis sammendrag

  Gene expression was studied in Atlantic cod fed two different diets, fish meal (FM) and dehulled and extracted soybean meal (SBM). RNAwas isolated from the distal part of the mid-intestine of Atlantic cod and suppression subtractive hybridization (SSH) was employed to screen for genes that showed changes in expression in response to the two dietary treatments. We made a cDNA subtracted library, isolated and sequenced 192 clones. Identification of 157 clones was predicted by BLAST. Most of the clones were previously unidentified in cod. Expression of 12 selected clones was further studied by quantitative PCR. Expression of four clones showing similarity to aminopeptidase N, transcobalamin I precursor, cytochrome P450 3A40, and ras-related nuclear protein was significantly up regulated in intestine of cod fed SBM compared to cod fed FM. A trend towards up regulation of a clone with similarity to fatty acid binding protein in SBM-fed cod was also observed. No significant differences in expression were observed for: transmembrane 4 superfamily protein member, polypeptide N-acetylgalactosaminyltransferase, glutathione peroxidase, peroxiredoxin 4, SEC61, F-BOX, and 14-3-3.

• Boqest, Andrew Craig; Noer, Agate; Sørensen, Anita Løvstad; Vekterud, Kristin & Collas, Philippe (2006). CpG Methylation Profiles of Endothelial Cell-Specific Gene Promoter Regions in Adipose Tissue Stem Cells Suggest Limited Differentiation Potential toward the Endothelial Cell Lineage. Stem Cells.  ISSN 1066-5099.

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• 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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