Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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GATA4 represses an ileal program of gene expression in the proximal small intestine by inhibiting the acetylation of histone H3, lysine 27.

ABSTRACT: GATA4 is expressed in the proximal 85% of small intestine where it promotes a proximal intestinal ('jejunal') identity while repressing a distal intestinal ('ileal') identity, but its molecular mechanisms are unclear. Here, we tested the hypothesis that GATA4 promotes a jejunal versus ileal identity in mouse intestine by directly activating and repressing specific subsets of absorptive enterocyte genes by modulating the acetylation of histone H3, lysine 27 (H3K27), a mark of active chromatin, at sites of GATA4 occupancy. Global analysis of mouse jejunal epithelium showed a statistically significant association of GATA4 occupancy with GATA4-regulated genes. Occupancy was equally distributed between down- and up-regulated targets, and occupancy sites showed a dichotomy of unique motif over-representation at down- versus up-regulated genes. H3K27ac enrichment at GATA4-binding loci that mapped to down-regulated genes (activation targets) was elevated, changed little upon conditional Gata4 deletion, and was similar to control ileum, whereas H3K27ac enrichment at GATA4-binding loci that mapped to up-regulated genes (repression targets) was depleted, increased upon conditional Gata4 deletion, and approached H3K27ac enrichment in wild-type control ileum. These data support the hypothesis that GATA4 both activates and represses intestinal genes, and show that GATA4 represses an ileal program of gene expression in the proximal small intestine by inhibiting the acetylation of H3K27. 2 samples were analyzed (1 ChIPseq, 1 input sample), control was done by confirming ChIP-qPCR on specific targets

ORGANISM(S): Mus musculus

SUBMITTER: Boaz Aronson

PROVIDER: E-GEOD-68957 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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GATA4 represses an ileal program of gene expression in the proximal small intestine by inhibiting the acetylation of histone H3, lysine 27.

Aronson B E BE Rabello Aronson S S Berkhout R P RP Chavoushi S F SF He A A Pu W T WT Verzi M P MP Krasinski S D SD

Biochimica et biophysica acta 20140527 11

GATA4 is expressed in the proximal 85% of small intestine where it promotes a proximal intestinal ('jejunal') identity while repressing a distal intestinal ('ileal') identity, but its molecular mechanisms are unclear. Here, we tested the hypothesis that GATA4 promotes a jejunal versus ileal identity in mouse intestine by directly activating and repressing specific subsets of absorptive enterocyte genes by modulating the acetylation of histone H3, lysine 27 (H3K27), a mark of active chromatin, at ...[more]

PMID: 24878542

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Project description:Background and Aims: Although the zinc finger transcription factor GATA4 has been implicated in regulating jejunal gene expression, the contribution of GATA4 in controlling jejunal physiology has not been addressed. Methods: We generated mice in which the Gata4 gene was specifically deleted in the small intestinal epithelium. Measurements of plasma cholesterol and phospholipids, intestinal absorption of dietary fat and cholesterol, and gene expression were performed on these animals. Results: Mice lacking GATA4 in the intestine displayed a dramatic block in their ability to absorb cholesterol and dietary fat. Comparison of the global gene expression profiles of control jejunum, control ileum, and GATA4 null jejunum by gene array analysis demonstrated that GATA4 null jejunum lost expression of 53% of the jejunal-specific gene set and gained expression of 47% of the set of genes unique to the ileum. These alterations in gene expression included a decrease in mRNAs encoding lipid and cholesterol transporters as well as an increase in mRNAs encoding proteins involved in bile acid absorption. Conclusion: Our data demonstrate that GATA4 is essential for jejunal function including fat and cholesterol absorption and confirm that GATA4 plays a pivotal role in determining jejunal versus ileal identity. Experiment Overall Design: Total RNA was harvested from the following sources and used to Affymetrix array analysis following manufacturer defined protocols: Experiment Overall Design: control jejunum (Gata4loxP/+VilCre), 3 male mice, adult (6-8 wk) Experiment Overall Design: mutant jejunum (Gata4loxP/-VilCre), 3 male mice, adult (6-8 wk) Experiment Overall Design: control ileum (Gata4loxP/+VilCre), 3 male mice, adult (6-8 wk). Experiment Overall Design: A total of nine Mouse Genome 430_2.0 arrays were hybridized for this study. Experiment Overall Design: Jejunum was defined as 10 cm from the pyloric sphincter, and ileum was defined as 1 cm from the cecum. The animals used to harvest control jejunum and ileum were independent of each other.

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GATA4 represses an ileal program of gene expression in the proximal small intestine by inhibiting the acetylation of histone H3, lysine 27.

Publications

GATA4 represses an ileal program of gene expression in the proximal small intestine by inhibiting the acetylation of histone H3, lysine 27.

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