Bhattacharya Saikat, Reddy Divya, Zhang Ning, Li Hua, Workman Jerry L
Stowers Institute for Medical Research, Kansas City, MO, United States.
Front Cell Dev Biol. 2022 Aug 10;10:945668. doi: 10.3389/fcell.2022.945668. eCollection 2022.
The methyltransferase SETD2 regulates cryptic transcription, alternative splicing, and the DNA damage response. It is mutated in a variety of cancers and is believed to be a tumor suppressor. Counterintuitively, despite its important role, SETD2 is robustly degraded by the proteasome keeping its levels low. Here we show that SETD2 accumulation results in a non-canonical deposition of the functionally important H3K36me3 histone mark, which includes its reduced enrichment over gene bodies and exons. This perturbed epigenetic landscape is associated with widespread changes in transcription and alternative splicing. Strikingly, contrary to its role as a tumor suppressor, excessive SETD2 results in the upregulation of cell cycle-associated pathways. This is also reflected in phenotypes of increased cell proliferation and migration. Thus, the regulation of SETD2 levels through its proteolysis is important to maintain its appropriate function, which in turn regulates the fidelity of transcription and splicing-related processes.
甲基转移酶SETD2调节隐蔽转录、可变剪接和DNA损伤反应。它在多种癌症中发生突变，被认为是一种肿瘤抑制因子。与直觉相反的是，尽管SETD2具有重要作用，但它会被蛋白酶体强烈降解，使其水平保持较低。在这里，我们表明SETD2的积累会导致功能重要的H3K36me3组蛋白标记的非经典沉积，这包括其在基因体和外显子上的富集减少。这种扰动的表观遗传景观与转录和可变剪接的广泛变化有关。引人注目的是，与其作为肿瘤抑制因子的作用相反，过量的SETD2会导致细胞周期相关通路的上调。这也反映在细胞增殖和迁移增加的表型中。因此，通过蛋白水解调节SETD2水平对于维持其适当功能很重要，而这反过来又调节转录和剪接相关过程的保真度。
