MED1 IDR deacetylation controls stress responsive genes through RNA Pol II recruitment.

IF 13.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Nature chemical biology Pub Date : 2025-10-23 DOI:10.1038/s41589-025-02035-7

Ran Lin,Yan Mo,Douglas Barrows,Wenbin Mei,Takashi Onikubo,Jianfeng Sun,Zhiguo Zhang,Effie Apostolou,Sohail F Tavazoie,Robert G Roeder

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Abstract

Cells fine-tune gene expression in response to cellular stress, a process critical for tumorigenesis. However, mechanisms governing stress-responsive transcription remain incompletely understood. This study shows that the MED1 subunit of the Mediator coactivator complex is acetylated in its intrinsically disordered region (IDR). Under stress, SIRT1 associates with the super elongation complex to deacetylate MED1 in promoter-proximal regions. The deacetylated (or acetylation-defective mutant) MED1 amplified stress-activated cytoprotective genes and rescued stress-suppressed growth-supportive genes in estrogen-receptor-positive breast cancer (ER+ BC) cells. Mechanistically, deacetylated MED1 promotes chromatin incorporation of RNA polymerase II (Pol II) through IDR-mediated interactions. Functionally, ER+ BC cells with deacetylated MED1 exhibit faster growth and enhanced stress resistance in culture and in an orthotopic mouse model. These findings advance our understanding of Pol II regulation under cellular stress and potentially suggest therapeutic strategies targeting oncogenic transcription driven by MED1 and Mediator.

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MED1 IDR去乙酰化通过RNA Pol II募集控制应激反应基因。

细胞调节基因表达以响应细胞应激，这是肿瘤发生的关键过程。然而，控制应激反应转录的机制仍然不完全清楚。本研究表明，中介共激活物复合物的MED1亚基在其内在无序区（IDR）发生乙酰化。在压力下，SIRT1与超延伸复合物结合，在启动子-近端区域使MED1去乙酰化。在雌激素受体阳性乳腺癌（ER+ BC）细胞中，去乙酰化（或乙酰化缺陷突变体）MED1扩增了应激激活的细胞保护基因，并挽救了应激抑制的生长支持基因。机制上，去乙酰化的MED1通过idr介导的相互作用促进RNA聚合酶II （Pol II）的染色质结合。在功能上，MED1去乙酰化的ER+ BC细胞在培养和原位小鼠模型中表现出更快的生长和增强的抗逆性。这些发现促进了我们对细胞应激下Pol II调控的理解，并可能提出针对MED1和Mediator驱动的致癌转录的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature chemical biology 生物-生化与分子生物学

CiteScore

23.90

自引率

1.40%

发文量

238

审稿时长

12 months

期刊介绍： Nature Chemical Biology stands as an esteemed international monthly journal, offering a prominent platform for the chemical biology community to showcase top-tier original research and commentary. Operating at the crossroads of chemistry, biology, and related disciplines, chemical biology utilizes scientific ideas and approaches to comprehend and manipulate biological systems with molecular precision. The journal embraces contributions from the growing community of chemical biologists, encompassing insights from chemists applying principles and tools to biological inquiries and biologists striving to comprehend and control molecular-level biological processes. We prioritize studies unveiling significant conceptual or practical advancements in areas where chemistry and biology intersect, emphasizing basic research, especially those reporting novel chemical or biological tools and offering profound molecular-level insights into underlying biological mechanisms. Nature Chemical Biology also welcomes manuscripts describing applied molecular studies at the chemistry-biology interface due to the broad utility of chemical biology approaches in manipulating or engineering biological systems. Irrespective of scientific focus, we actively seek submissions that creatively blend chemistry and biology, particularly those providing substantial conceptual or methodological breakthroughs with the potential to open innovative research avenues. The journal maintains a robust and impartial review process, emphasizing thorough chemical and biological characterization.