Heterochromatin, a key component of the eukaryotic nucleus, is fundamental to the regulation of genome stability, gene expression and cellular functions. However, the factors and mechanisms involved in heterochromatin formation and maintenance still remain largely unknown. Here, we show that insulin receptor tyrosine kinase substrate (IRTKS), an I-BAR domain protein, is indispensable for constitutive heterochromatin formation via liquid‒liquid phase separation (LLPS). In particular, IRTKS droplets can infiltrate heterochromatin condensates composed of HP1α and diverse DNA-bound nucleosomes. IRTKS can stabilize HP1α by recruiting the E2 ligase Ubc9 to SUMOylate HP1α, which enables it to form larger phase-separated droplets than unmodified HP1α. Furthermore, IRTKS deficiency leads to loss of heterochromatin, resulting in genome-wide changes in chromatin accessibility and aberrant transcription of repetitive DNA elements. This leads to activation of cGAS-STING pathway and type-I interferon (IFN-I) signaling, as well as to the induction of cellular senescence and senescence-associated secretory phenotype (SASP) responses. Collectively, our findings establish a mechanism by which IRTKS condensates consolidate constitutive heterochromatin, revealing an unexpected role of IRTKS as an epigenetic mediator of cellular senescence.

中文翻译：

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IRTKS 凝聚物的异染色质形成和重塑抵消了细胞衰老。


异染色质是真核细胞核的关键成分，是调节基因组稳定性、基因表达和细胞功能的基础。然而，异染色质形成和维持所涉及的因素和机制在很大程度上仍然未知。在这里，我们表明胰岛素受体酪氨酸激酶底物 （IRTKS） 是一种 I-BAR 结构域蛋白，对于通过液相分离 （LLPS） 形成组成型异染色质是必不可少的。特别是，IRTKS 液滴可以浸润由 HP1α 和多种 DNA 结合核小体组成的异染色质凝聚物。IRTKS 可以通过募集 E2 连接酶 Ubc9 来稳定 HP1α，使其能够形成比未修饰的 HP1α 更大的相分离液滴。此外，IRTKS 缺陷导致异染色质丢失，导致染色质可及性的全基因组变化和重复 DNA 元件的异常转录。这导致 cGAS-STING 通路和 I 型干扰素 （IFN-I） 信号转导的激活，以及诱导细胞衰老和衰老相关分泌表型 （SASP） 反应。总的来说，我们的研究结果建立了一种机制，即 IRTKS 缩合物巩固组成型异染色质，揭示了 IRTKS 作为细胞衰老表观遗传介质的意想不到的作用。