SPIN1 通过其 IDR 的相分离促进了组蛋白甲基化读出和肿瘤发生。

IF 5.3 2区 生物学 Q2 CELL BIOLOGY Journal of Molecular Cell Biology Pub Date : 2024-05-22 DOI:10.1093/jmcb/mjae024
Yukun Wang, Yuhan Chen, Mengyao Li, Jiayue Wang, Yuhan Jiang, Rong Xie, Yifeng Zhang, Zhihua Li, Zhenzhen Yan, Chen Wu
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引用次数: 0

摘要

Spindlin1(SPIN1)是一种独特的多价组蛋白修饰阅读器,在核糖体 RNA 转录、染色体分离和肿瘤发生中发挥作用。然而,SPIN1 N 端延长区域的功能一直不清楚。在这里,我们发现 SPIN1 可以通过其 N 端内在无序区(IDR)在体外和体内形成相分离的液态凝结物。SPIN1 的相分离将组蛋白甲基转移酶 MLL1 吸引到相同的凝聚物上,并富集 H3K4 甲基化标记。这一过程也促进了 SPIN1 与 H3K4me3 的结合,并激活肿瘤发生相关基因。此外,SPIN1-IDR 还能增强 SPIN1 的全基因组染色质结合,并促进其定位到与 MAPK 信号通路相关的基因上。这些发现为我们提供了关于IDR在调控SPIN1活性方面的生物学功能的新见解,并揭示了SPIN1-IDR在组蛋白甲基化读出方面以前未被认识到的作用。我们的研究揭示了 SPIN1 适当的生物物理特性在促进基因表达中的关键作用,并将相分离与肿瘤发生联系起来,这为理解 SPIN1 的功能提供了一个新的视角。
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Phase separation of SPIN1 through its IDR facilitates histone methylation readout and tumorigenesis.

Spindlin1 (SPIN1) is a unique multivalent histone modification reader that plays a role in ribosomal RNA transcription, chromosome segregation, and tumorigenesis. However, the function of the extended N-terminal region of SPIN1 has remained unclear. Here, we discovered that SPIN1 can form phase-separated and liquid-like condensates both in vitro and in vivo through its N-terminal intrinsically disordered region (IDR). The phase separation of SPIN1 recruits the histone methyltransferase MLL1 to the same condensates and enriches the H3K4 methylation marks. This process also facilitates the binding of SPIN1 to H3K4me3 and activates tumorigenesis-related genes. Moreover, SPIN1-IDR enhances the genome-wide chromatin binding of SPIN1 and facilitates its localization to genes associated with the MAPK signaling pathway. These findings provide new insights into the biological function of the IDR in regulating SPIN1 activity and reveal a previously unrecognized role of SPIN1-IDR in histone methylation readout. Our study uncovers the crucial role of appropriate biophysical properties of SPIN1 in facilitating gene expression and links phase separation to tumorigenesis, which provides a new perspective for understanding the function of SPIN1.

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来源期刊
CiteScore
9.60
自引率
1.80%
发文量
1383
期刊介绍: The Journal of Molecular Cell Biology ( JMCB ) is a full open access, peer-reviewed online journal interested in inter-disciplinary studies at the cross-sections between molecular and cell biology as well as other disciplines of life sciences. The broad scope of JMCB reflects the merging of these life science disciplines such as stem cell research, signaling, genetics, epigenetics, genomics, development, immunology, cancer biology, molecular pathogenesis, neuroscience, and systems biology. The journal will publish primary research papers with findings of unusual significance and broad scientific interest. Review articles, letters and commentary on timely issues are also welcome. JMCB features an outstanding Editorial Board, which will serve as scientific advisors to the journal and provide strategic guidance for the development of the journal. By selecting only the best papers for publication, JMCB will provide a first rate publishing forum for scientists all over the world.
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