Kristin Vekterud

• Fan, Qiong; Nørgaard, Rikke Christine; Grytten, Ivar; Ness, Cecilie; Lucas, Christin & Vekterud, Kristin [Show all 15 contributors for this article] (2020). LXRα Regulates ChREBPα Transactivity in a Target Gene-Specific Manner through an Agonist-Modulated LBD-LID Interaction. Cells. 9(5), p. 1–26. doi: 10.3390/cells9051214. Full text in Research Archive Show summary

  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 [Show all 15 contributors for this article] (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. Full text in Research Archive Show summary

  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 [Show all 10 contributors for this article] (2017). PML protein organizes heterochromatin domains where it regulates histone H3.3 deposition by ATRX/DAXX. Genome Research. ISSN 1088-9051. 27(6), p. 913–921. doi: 10.1101/gr.215830.116. Full text in Research Archive Show summary

  Maintenance of chromatin homeostasis involves proper delivery of histone variants to the genome. The interplay between different chaperones regulating the supply of histone variants to distinct chromatin domains remains largely undeciphered. We report a role of promyelocytic leukemia (PML) protein in the routing of histone variant H3.3 to chromatin and in the organization of megabase-size heterochromatic PML-associated domains that we call PADs. Loss of PML alters the heterochromatic state of PADs by shifting the histone H3 methylation balance from K9me3 to K27me3. Loss of PML impairs deposition of H3.3 by ATRX and DAXX in PADs but preserves the H3.3 loading function of HIRA in these regions. Our results unveil an unappreciated role of PML in the large-scale organization of chromatin and demonstrate a PML-dependent role of ATRX/DAXX in the deposition of H3.3 in PADs. Our data suggest that H3.3 loading by HIRA and ATRX-dependent H3K27 trimethylation constitute mechanisms ensuring maintenance of heterochromatin when the integrity of these domains is compromised.

• Rønningen, Torunn; Shah, Akshay; Oldenburg, Anja; Vekterud, Kristin; Delbarre, Erwan & Moskaug, Jan Øivind [Show all 7 contributors for this article] (2015). Prepatterning of differentiation-driven nuclear lamin A/C-associated chromatin domains by GlcNAcylated histone H2B. Genome Research. ISSN 1088-9051. 25(12), p. 1825–1835. doi: 10.1101/gr.193748.115. Full text in Research Archive Show summary

  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.

• Sørensen, Anita Løvstad; Barrand, Sanna Kristiina; West, Franklin D.; Vekterud, Kristin; Boquest, Andrew Craig & Åhrlund-Richter, Lars [Show all 8 contributors for this article] (2010). Lineage-Specific Promoter DNA Methylation Patterns Segregate Adult Progenitor Cell Types. Stem Cells and Development. ISSN 1547-3287. 19(8), p. 1257–1266. doi: 10.1089/scd.2009.0309. Full text in Research Archive
• Frøystad-Saugen, Marianne K.; Lilleeng, Einar; Bakke-McKellep, Anne Marie; Vekterud, Kristin; Valen, Elin C. & Hemre, Gro-Ingunn [Show all 7 contributors for this article] (2009). Distal intestinal gene expression in Atlantic salmon (Salmo salar L.) fed genetically modified maize. Aquaculture Nutrition. ISSN 1353-5773. 15(1), p. 104–115. doi: 10.1111/j.1365-2095.2008.00572.x. Full text in Research Archive
• 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), p. 204–214. doi: 10.1111/j.1365-2095.2007.00519.x. Full text in Research Archive
• 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), p. 852–861. Full text in Research Archive
• 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), p. 269–283. Full text in Research Archive Show summary

  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. Full text in Research Archive

View all works in NVA

• Fan, Qiong; Nørgaard, Rikke Christine; Grytten, Ivar; Ness, Cecilie Maria; Lucas, Christin & Vekterud, Kristin [Show all 15 contributors for this article] (2019). LXRα interacts with the glucose-sensing transcription factor ChREBPα to regulate its transcriptional activity. Full text in Research Archive Show summary

  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.

View all works in NVA