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首页> 外文期刊>Biochimica et Biophysica Acta. Gene Regulatory Mechanisms >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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GATA4 represses an ileal program of gene expression in the proximal small intestine by inhibiting the acetylation of histone H3, lysine 27

机译:GATA4通过抑制组蛋白H3赖氨酸的乙酰化来抑制近端小肠中基因表达的回肠程序

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摘要

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.
机译:GATA4在小肠的近端85%中表达,在促进近端肠(“空肠”)身份同时抑制远端肠(“回肠”)身份的同时,其分子机制尚不清楚。在这里,我们测试了以下假设:GATA4通过调节组蛋白H3赖氨酸27(H3K27)(活性染色质的标记)的乙酰化来直接激活和抑制吸收性肠上皮细胞基因的特定子集,从而在小鼠肠道中促进空肠与回肠的同一性。 GATA4占用率。小鼠空肠上皮的整体分析表明,GATA4的占有率与GATA4调控的基因有统计学意义的关联。在下调和上调的靶标之间平均占据着分布,在下调和上调的基因上,占据位点显示出独特的基序过度代表的二分法。映射到下调基因(激活靶标)的GATA4结合位点处的H3K27ac富集升高,有条件的Gata4缺失后几乎没有变化,并且与对照回肠相似,而映射到上调基因的GATA4结合位点处的H3K27ac富集(抑制目标)耗尽,有条件的Gata4删除后增加,并在野生型对照回肠中达到H3K27ac富集。这些数据支持GATA4既激活又抑制肠基因的假说,并表明GATA4通过抑制H3K27的乙酰化而抑制近端小肠中基因表达的回肠程序。

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