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HSF1 的磷酸化通过 TRRAP-TIP60 复合物建立了一个活跃的染色质状态，并促进了肿瘤的发生。

HSF1 phosphorylation establishes an active chromatin state via the TRRAP-TIP60 complex and promotes tumorigenesis.

机构信息

Department of Biochemistry and Molecular Biology, Yamaguchi University School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi, 755-8505, Japan.

Department of Omics and Systems Biology, Graduate School of Medical and Dental Sciences, Niigata University, Ichibancho 757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.

出版信息

Nat Commun. 2022 Jul 29;13(1):4355. doi: 10.1038/s41467-022-32034-4.

DOI:10.1038/s41467-022-32034-4
PMID:35906200
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9338313/
Abstract

Transcriptional regulation by RNA polymerase II is associated with changes in chromatin structure. Activated and promoter-bound heat shock transcription factor 1 (HSF1) recruits transcriptional co-activators, including histone-modifying enzymes; however, the mechanisms underlying chromatin opening remain unclear. Here, we demonstrate that HSF1 recruits the TRRAP-TIP60 acetyltransferase complex in HSP72 promoter during heat shock in a manner dependent on phosphorylation of HSF1-S419. TRIM33, a bromodomain-containing ubiquitin ligase, is then recruited to the promoter by interactions with HSF1 and a TIP60-mediated acetylation mark, and cooperates with the related factor TRIM24 for mono-ubiquitination of histone H2B on K120. These changes in histone modifications are triggered by phosphorylation of HSF1-S419 via PLK1, and stabilize the HSF1-transcription complex in HSP72 promoter. Furthermore, HSF1-S419 phosphorylation is constitutively enhanced in and promotes proliferation of melanoma cells. Our results provide mechanisms for HSF1 phosphorylation-dependent establishment of an active chromatin status, which is important for tumorigenesis.

摘要

RNA 聚合酶 II 的转录调控与染色质结构的变化有关。激活的和与启动子结合的热休克转录因子 1（HSF1）招募转录共激活因子，包括组蛋白修饰酶；然而，染色质开放的机制尚不清楚。在这里，我们证明在热休克期间，HSF1 通过依赖于 HSF1-S419 磷酸化的方式在 HSP72 启动子上募集 TRRAP-TIP60 乙酰转移酶复合物。然后，含有溴结构域的泛素连接酶 TRIM33 通过与 HSF1 和 TIP60 介导的乙酰化标记相互作用被募集到启动子上，并与相关因子 TRIM24 合作，对组蛋白 H2B 的 K120 进行单泛素化。这些组蛋白修饰的变化是由 HSF1-S419 通过 PLK1 的磷酸化触发的，并稳定 HSP72 启动子上的 HSF1 转录复合物。此外，HSF1-S419 磷酸化在黑色素瘤细胞中持续增强，并促进其增殖。我们的研究结果为 HSF1 磷酸化依赖性建立活性染色质状态提供了机制，这对肿瘤发生很重要。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adf2/9338313/41fe68864208/41467_2022_32034_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adf2/9338313/cb95c5a4ebad/41467_2022_32034_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adf2/9338313/7db2816aee68/41467_2022_32034_Fig2_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adf2/9338313/4118935aeba0/41467_2022_32034_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adf2/9338313/3b51b561a24e/41467_2022_32034_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adf2/9338313/5b8e5e94adcb/41467_2022_32034_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adf2/9338313/41fe68864208/41467_2022_32034_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adf2/9338313/cb95c5a4ebad/41467_2022_32034_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adf2/9338313/7db2816aee68/41467_2022_32034_Fig2_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adf2/9338313/3b51b561a24e/41467_2022_32034_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adf2/9338313/5b8e5e94adcb/41467_2022_32034_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/adf2/9338313/41fe68864208/41467_2022_32034_Fig7_HTML.jpg

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