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Histone methylation and transcription factor binding during intestinal cell differentation

ABSTRACT: Cell differentiation requires epigenetic modulation of tissue-specific genes and activities of master transcriptional regulators, which are recognized for their dominant control over cellular programs. Using novel epigenomic methods, we characterized enhancer elements specifically modified in differentiating intestinal epithelial cells and found enrichment of transcription factor-binding motifs corresponding to CDX2, a master regulator of the intestine. Directed investigation revealed surprising lability in CDX2 occupancy of the genome, with redistribution from hundreds of sites occupied only in progenitors to thousands of new sites in mature cells. Knockout mice confirmed distinct Cdx2 requirements in dividing and differentiated adult intestinal cells, including responsibility for the active enhancer configuration associated with maturity. Dynamic CDX2 occupancy corresponds with condition-specific gene expression and, importantly, to differential co-occupancy with other tissue-restricted transcription factors: HNF4A in mature cells and GATA6 in progenitors. These results reveal dynamic, context-specific functions and mechanisms of a master transcription factor within a cell lineage.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE23436 | GEO | 2010/11/17

SECONDARY ACCESSION(S): PRJNA131107

REPOSITORIES: GEO

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Histone methylation and transcription factor binding during intestinal cell differentation

Project description:Cell differentiation requires epigenetic modulation of tissue-specific genes and activities of master transcriptional regulators, which are recognized for their dominant control over cellular programs. Using novel epigenomic methods, we characterized enhancer elements specifically modified in differentiating intestinal epithelial cells and found enrichment of transcription factor-binding motifs corresponding to CDX2, a master regulator of the intestine. Directed investigation revealed surprising lability in CDX2 occupancy of the genome, with redistribution from hundreds of sites occupied only in progenitors to thousands of new sites in mature cells. Knockout mice confirmed distinct Cdx2 requirements in dividing and differentiated adult intestinal cells, including responsibility for the active enhancer configuration associated with maturity. Dynamic CDX2 occupancy corresponds with condition-specific gene expression and, importantly, to differential co-occupancy with other tissue-restricted transcription factors: HNF4A in mature cells and GATA6 in progenitors. These results reveal dynamic, context-specific functions and mechanisms of a master transcription factor within a cell lineage. H3K4me2, CDX2, GATA6, and HNF4A ChIP-seq patterns were mapped in proliferating and 26 day post-confluent (differentatied) Caco-2 intestinal cell lines and compared to published expression data or newly generated Cdx2 knockout mouse intestine expression data

2010-11-17 | E-GEOD-23436 | biostudies-arrayexpress

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Distinct processes and transcriptional targets underlie CDX2 requirements in intestinal stem cells and differentiated villus cells

Project description:To define target genes of the intestine-restricted transcription factor (TF) CDX2 in intestinal stem cells, we performed chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-Seq). We used RNA-sequencing to profile gene expression changes during cell differentiation from mouse intestinal stem cells to mature villus cells, as well as genes perturbed in intestinal stem cells upon loss of Cdx2. We find thousands of genes that change in expression during cell differentiation, including known stem cell and mature markers. Upon loss of Cdx2, hundreds of genes are up and down-regulated in intestinal stem cells, some of which are also bound by CDX2 nearby and constitute candidate direct target genes. CDX2 ChIP-Seq analysis of isolated mouse intestinal stem cells. RNA seq analysis of control mouse villus cells, control intestinal stem cells and Cdx2-deleted intestinal stem cells.

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TCF4 and CDX2, major transcription factors for intestinal function, converge on the same cis-regulatory regions

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Project description:Important lineage regulators, such as the intestinal lineage regulator CDX2, can function over the timespan of intestinal development. The consequences of CDX2 knockout in the embryo versus in the adult are quite distinct. The data below provide a rationale for these divergent transcription factor functions in distinct developmental contexts, with unique binding patterns of CDX2 observed via ChIP-seq and unique gene regulatory targets defined via RNA-seq. The dynamic gene regulatory program controlled by CDX2 is conserved in mice and humans.

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COLO320 cells: siCDX2 vs. non-targeting control

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