Dynamic RNA Polymerase II Recruitment Drives Differentiation of the Intestine under the direction of HNF4.
Dynamic RNA Polymerase II Recruitment Drives Differentiation of the Intestine under the direction of HNF4.
复制标题
动态 RNA 聚合酶 II 募集在 HNF4 的指导下驱动肠道分化。
DOI：
10.1101/2023.11.08.566322
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Verzi,MichaelP
中科院分区：
文献类型：
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作者：
Vemuri,Kiranmayi;Kumar,Sneha;Chen,Lei;Verzi,MichaelP
末端分化需要转录组的大规模重组。在肠分化过程中，随着细胞从隐窝中的祖细胞转变为绒毛中的分化细胞，近4000个基因的表达模式发生改变。我们确定了RNA聚合酶II（Pol II）的基因启动子的动态招募作为体内肠分化过程中转录组转变的主要驱动因素。增强子-启动子环相互作用的变化伴随着动态Pol II募集，并且依赖于促分化转录因子HNF 4。使用遗传功能丧失，ChIP-seq和IP质谱，我们证明了HNF 4与染色质重塑和环稳定蛋白合作，并促进了数百个对分化至关重要的基因的Pol II招募。我们还探索了驱动分化基因表达的替代机制，并发现Pol II的暂停释放和转录后mRNA稳定性调节差异表达基因的较小子集。这些研究提供了对更新的成体组织中的分化机制的见解。
Terminal differentiation requires a massive restructuring of the transcriptome. During intestinal differentiation, the expression patterns of nearly 4000 genes are altered as cells transition from progenitor cells in crypts to differentiated cells in villi. We identified dynamic recruitment of RNA Polymerase II (Pol II) to gene promoters as the primary driver of transcriptomic shifts during intestinal differentiation in vivo. Changes in enhancer-promoter looping interactions accompany dynamic Pol II recruitment and are dependent upon HNF4, a pro-differentiation transcription factor. Using genetic loss-of- function, ChIP-seq and IP mass spectrometry, we demonstrate that HNF4 collaborates with chromatin remodelers and loop-stabilizing proteins and facilitates Pol II recruitment at hundreds of genes pivotal to differentiation. We also explore alternate mechanisms which drive differentiation gene expression and find pause-release of Pol II and post- transcriptional mRNA stability regulate smaller subsets of differentially expressed genes. These studies provide insights into the mechanisms of differentiation in a renewing adult tissue.