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解析 YAP 依赖性转录在肝脏中的作用。

Decoding YAP dependent transcription in the liver.

机构信息

Center for Genomic Science of CGS@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy.

Department of Experimental Oncology, European Institute of Oncology (IEO)-IRCCS, Milan, Italy.

出版信息

Nucleic Acids Res. 2022 Aug 12;50(14):7959-7971. doi: 10.1093/nar/gkac624.

DOI:10.1093/nar/gkac624
PMID:35871292
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9371928/
Abstract

The transcriptional coactivator YAP is emerging as a master regulator of cell growth. In the liver, YAP activity is linked to hepatomegaly, regeneration, dedifferentiation, and aggressive tumor growth. Here we present genomic studies to address how YAP may elicit such profound biological changes in murine models. YAP bound the genome in a TEAD-dependent manner, either at loci constitutively occupied by TEAD or by pioneering enhancers, which comprised a fraction of HNF4a/FOXA-bound embryonic enhancers active during embryonic development but silent in the adult. YAP triggered transcription on promoters by recruiting BRD4, enhancing H3K122 acetylation, and promoting RNApol2 loading and pause-release. YAP also repressed HNF4a target genes by binding to their promoters and enhancers, thus preventing RNApol2 pause-release. YAP activation led to the induction of hepatocyte proliferation, accompanied by tissue remodeling, characterized by polarized macrophages, exhausted T-lymphocytes and dedifferentiation of endothelial cells into proliferative progenitors. Overall, these analyses suggest that YAP is a master regulator of liver function that reshapes the enhancer landscape to control transcription of genes involved in metabolism, proliferation, and inflammation, subverts lineage specification programs by antagonizing HNF4a and modulating the immune infiltrate and the vascular architecture of the liver.

摘要

转录共激活因子 YAP 正在成为细胞生长的主要调节因子。在肝脏中，YAP 的活性与肝肿大、再生、去分化和侵袭性肿瘤生长有关。在这里，我们进行了基因组研究，以探讨 YAP 如何在小鼠模型中引发如此深刻的生物学变化。YAP 以 TEAD 依赖性的方式结合基因组，要么在 TEAD 持续占据的基因座上结合，要么在先驱增强子上结合，这些增强子包含了一部分在胚胎发育过程中活跃但在成年时沉默的 HNF4a/FOXA 结合的胚胎增强子。YAP 通过招募 BRD4 来启动启动子的转录，增强 H3K122 乙酰化，并促进 RNApol2 加载和暂停释放。YAP 还通过结合其启动子和增强子来抑制 HNF4a 靶基因，从而阻止 RNApol2 暂停释放。YAP 的激活导致肝细胞增殖的诱导，伴随着组织重塑，其特征是极化的巨噬细胞、耗竭的 T 淋巴细胞和内皮细胞向增殖前体的去分化。总的来说，这些分析表明，YAP 是肝脏功能的主要调节因子，它重塑增强子景观，以控制参与代谢、增殖和炎症的基因的转录，通过拮抗 HNF4a 和调节免疫浸润和肝脏的血管结构来颠覆谱系特化程序。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b721/9371928/235ac5b8ec31/gkac624fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b721/9371928/d861837e2d43/gkac624fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b721/9371928/f7fd9741875f/gkac624fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b721/9371928/66ce8a7b3b4b/gkac624fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b721/9371928/320331fc35ad/gkac624fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b721/9371928/7fdc38cd9021/gkac624fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b721/9371928/69d4bf61b5c5/gkac624fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b721/9371928/235ac5b8ec31/gkac624fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b721/9371928/d861837e2d43/gkac624fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b721/9371928/f7fd9741875f/gkac624fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b721/9371928/66ce8a7b3b4b/gkac624fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b721/9371928/320331fc35ad/gkac624fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b721/9371928/7fdc38cd9021/gkac624fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b721/9371928/69d4bf61b5c5/gkac624fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b721/9371928/235ac5b8ec31/gkac624fig7.jpg

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2
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3
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Cell Mol Life Sci. 2024 Jul 9;81(1):295. doi: 10.1007/s00018-024-05328-7.
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5
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