Intrachromosomal interactions across the intestinal crypt-villus axis and the imapct on chromatin looping upon HNF4 loss
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE148691 | GEO | 2021/01/16
REPOSITORIES: GEO
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Project description:The mechanisms underlying intestinal epithelial differentiation are essential for maintaining intestinal health. Gene expression analysis reveals vast changes in the transcriptome as cells transition from crypts to villi, impacting nearly 4000 genes. The regulatory mechanisms driving transcriptome shifts during intestinal differentiation remain incompletely understood. Using ChIP-seq and multi-omic analyses, we have identified differential recruitment of Pol II to gene promoters as the primary driver of transcriptomic shifts during differentiation. Using genetic loss-of-function we show that HNF4, a crucial pro-differentiation transcription factor, is required for recruitment of Pol II to hundreds of genes that are activated during differentiation. Dynamic Pol II recruitment corresponds to dynamic enhancer-promoter looping and chromatin remodeling events, indicating a multi-step mechanism driving differentiation gene expression. Additional regulatory mechanisms, such as differential Pol II pause-release and post-transcriptional processes, may govern specific subsets of differentially expressed genes. In summary, our findings emphasize the central role of Pol II recruitment as the major regulator of intestinal differentiation and highlight the significance of HNF4 in this complex process.
2023-11-08 | GSE244918 | GEO
Project description:Intrachromosomal interactions across the intestinal crypt-villus axis and the imapct on chromatin looping upon HNF4 loss
| PRJNA625437 | ENA
Project description:HNF4 paralogs are redundantly required for proper villus elongation, differentiation and maturation in the developing gut. We find 5,391 chromatin regions become inaccessible upon HNF4 loss, and HNF4 binding sequences are most enriched in these regions. Genes nearby these 5,391 HNF4 dependent regions are associated with villus differentiation/maturation.
2019-07-29 | GSE128674 | GEO
Project description:Genes encoding transcription factors function as hubs in gene regulatory networks because they encode DNA-binding proteins, which bind to promoters that carry their binding sites. In the present work we have studied gene regulatory networks defined by genes with transcripts belonging to different mRNA abundance classes in the small intestinal epithelial cell. The focus is the rewiring that occurs in transcription factor hubs in these networks during the differentiation of the small intestinal epithelial cell while it migrates along the crypt-villus axis and during its development from a fetal endodermal cell to a mature adult villus epithelial cell. We have generated transcriptome data for mouse small intestinal villus, crypt and fetal intestinal epithelial cells. In addition we have generated metabolome data from crypt and villus cells. Our results show that the intestinal crypt transcription factor hubs that are rewired during differentiation are involved in the cell cycle process (E2F, NF-Y) and stem cell maintenance (c-Myc). In contrast the villi are dominated by a HNF-4 villus hub, which is rewired during differentiation by the addition of network genes with relevance for lipoprotein synthesis and lipid absorption. Moreover, we have identified a villus NF-kB hub, which was revealed by comparison of the villus and endoderm transcriptomes. The rewiring of the NF-kB villus hub during intestinal development reflects transcriptional activity established by host and microflora interactions. To aid in the mining of our results we have developed a web portal (http://gastro.imbg.ku.dk/mousecv/) allowing easy linkage between the transcriptomic data, biological processes and functions. Experiment Overall Design: Four different sample categories were analyzed. Experiment Overall Design: 1) Small intestinal crypts isolated form 12-weeks old C57BL/6 mice. These samples are in triplicates. Experiment Overall Design: 2) Small intestinal villi isolated form 12-weeks old C57BL/6 mice. These samples are in triplicates. Experiment Overall Design: 3) Embryonic day 12 mesenchyme. These samples are in quadruplicate. each sample is derived from a pool of mesenchymes (10-40) Experiment Overall Design: 4) Embryonic day 12 endoderm. These samples are in quadruplicate. each sample is derived from a pool of endoderms (10-40)
2008-06-12 | E-GEOD-3216 | biostudies-arrayexpress
Project description:Genes encoding transcription factors function as hubs in gene regulatory networks because they encode DNA-binding proteins, which bind to promoters that carry their binding sites. In the present work we have studied gene regulatory networks defined by genes with transcripts belonging to different mRNA abundance classes in the small intestinal epithelial cell. The focus is the rewiring that occurs in transcription factor hubs in these networks during the differentiation of the small intestinal epithelial cell while it migrates along the crypt-villus axis and during its development from a fetal endodermal cell to a mature adult villus epithelial cell. We have generated transcriptome data for mouse small intestinal villus, crypt and fetal intestinal epithelial cells. In addition we have generated metabolome data from crypt and villus cells. Our results show that the intestinal crypt transcription factor hubs that are rewired during differentiation are involved in the cell cycle process (E2F, NF-Y) and stem cell maintenance (c-Myc). In contrast the villi are dominated by a HNF-4 villus hub, which is rewired during differentiation by the addition of network genes with relevance for lipoprotein synthesis and lipid absorption. Moreover, we have identified a villus NF-kB hub, which was revealed by comparison of the villus and endoderm transcriptomes. The rewiring of the NF-kB villus hub during intestinal development reflects transcriptional activity established by host and microflora interactions. To aid in the mining of our results we have developed a web portal (http://gastro.imbg.ku.dk/mousecv/) allowing easy linkage between the transcriptomic data, biological processes and functions. Keywords: Cell type comparison
2005-11-29 | GSE3216 | GEO
Project description:We find that HNF4G is an intestine-particular HNF4 paralog, and works redundantly with HNF4A for driving intestinal differentiation by controlling chromatin accessibility and regulating thousands of transcripts particular to differentiated cells. Without HNF4s, cells fail to achieve a differentiated state. A positive feedback loop between HNF4 transcriptional regulation and BMP/SMAD signaling stabilizes differentiation, and the two inputs cooperatively activate differentiation gene expression.
2019-04-08 | GSE112946 | GEO
Project description:To define changes in gene expression resulting from loss of hnf4 in the small intestine. Keywords: genetic modification
2005-12-31 | GSE3124 | GEO
Project description:Background and Aims: HNF4? is a nuclear hormone receptor transcription factor that has been shown to be required for hepatocyte differentiation and development of the liver. It has also been implicated in regulating expression of genes that act in the epithelium of the lower gastrointestinal tract. This implied that HNF4? might be required for development of the gut. Methods: We generated mouse embryos in which Hnf4? was ablated in the epithelial cells of the fetal colon using Cre-loxP technology. Embryos were examined using a combination of histology, immunohistochemistry, gene array and RT-PCR, and chromatin immunoprecipitation analyses to define the consequence of loss of HNF4? on colon development. Results: Embryos could be generated until E18.5 that lacked HNF4? in their colon. Although, early stages of colonic development occurred, HNF4? null colons failed to form normal crypts. In addition, goblet cell maturation was perturbed and expression of an array of genes that encode proteins with diverse roles in colon function was disrupted. Several genes whose expression in the colon was dependent on HNF4? contained HNF4?âbinding sites sequences within putative transcriptional regulatory regions and a subset of these sites were occupied by HNF4? in vivo. Conclusion: HNF4? is a transcription factor that is essential for development of the mammalian colon, regulates goblet cell maturation and is required for expression of genes that control normal colon function and epithelial cell differentiation. Experiment Overall Design: COMPARISON OF 3 MUTANT TO 2 CONTROL COLONS.
2008-06-12 | E-GEOD-3116 | biostudies-arrayexpress
Project description:To define changes in gene expression resulting from loss of hnf4 in the small intestine. Experiment Overall Design: hnf4 null intestines were generated by breeding hnf4loxp mice to vill-cre mice. Animals appeared to be healthy. Gene arrays were performed on two null and two control intestines.
2008-06-12 | E-GEOD-3124 | biostudies-arrayexpress
Project description:We analyzed gene expression profiles in isolated mouse LGR5+ intestinal stem cells, lineage-specific enterocyte and secretory progenitors, and terminally differentiated villus enterocytes. Gene Ontology analyses of cell type-specific transcripts indicated their expected biological functions. We hybridized Affmetrix 430A 2.0 mouse microarrays with processed RNA isolated from purified Lgr5+ intestinal stem cells, secretory (Sec-Pro) and enterocyte (Ent-Pro) crypt progenitors, and mature villus enterocytes (ENT).
2014-01-06 | E-GEOD-51398 | biostudies-arrayexpress