Abstract：
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.
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转录中起作用，染色体分离,和肿瘤发生。然而,SPIN1延伸N末端区域的功能尚不清楚.这里,我们发现SPIN1可以通过其N端固有无序区（IDR）在体外和体内形成相分离和液状缩合物。SPIN1的相分离将组蛋白甲基转移酶MLL1募集到相同的缩合物中，并富集了H3K4甲基化标记。该过程还促进SPIN1与H3K4me3的结合并激活肿瘤发生相关基因。此外，SPIN1-IDR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。这些发现为IDR在调节SPIN1活性中的生物学功能提供了新的见解，并揭示了SPIN1-IDR在组蛋白甲基化读出中的先前未被识别的作用。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和连接阶段分离与肿瘤发生中的关键作用。这为理解SPIN1的功能提供了新的视角。
