小柯机器人

美国哈佛医学院Danesh Moazed团队近期取得重要工作进展，他们研究发现Rixosomal RNA降解促进了Polycomb靶基因的沉默。该研究成果2022年3月30日在线发表于《自然》杂志上。

在这里，研究人员表明表明rixosome有助于沉默人类细胞中的许多Polycomb靶标。rixosome与人类PRC复合物结合，在Polycomb靶基因的启动子上富集。rixosome或Polycomb的缺失会导致Polycomb靶基因上RNA聚合酶的积累。研究人员在PRC1的RING1B亚基中发现了点突变，该突变破坏了PRC1和rixosome之间的相互作用，并导致沉默减少，这表明rixosome直接招募到染色质是沉默所必需的。

最后，研究人员证明了RNA内切酶和核糖核酸激酶的活性以及下游的XRN2外切核糖核酸酶的活性是沉默所必需的。XRN2外切核糖核酸酶可以降解核糖核酸中含有5'单磷酸基团的RNA。他们的发现表明，从裂变酵母到人类，新生RNA的rixosomal降解是保守的，在人类细胞兼性异染色质的RNA降解中起主要作用。

据悉，多梳抑制复合物1和2 (PRC1和PRC2)是组蛋白修饰和结合复合物，可介导兼性异染色质的形成，是发育基因沉默和维持细胞命运所必需的。在分裂酵母中，RNA衰变的多种途径共同作用以建立和维持异染色质，包括最近发现的一种称为rixosome或RIX1复合物的保守RNA降解复合物的作用。RNA降解是否在哺乳动物异染色质的稳定性中也有作用仍不清楚。

附：英文原文

Title: Rixosomal RNA degradation contributes to silencing of Polycomb target genes

Author: Zhou, Haining, Stein, Chad B., Shafiq, Tiasha A., Shipkovenska, Gergana, Kalocsay, Marian, Paulo, Joao A., Zhang, Jiuchun, Luo, Zhenhua, Gygi, Steven P., Adelman, Karen, Moazed, Danesh

Issue&Volume: 2022-03-30

Abstract: Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) are histone-modifying and -binding complexes that mediate the formation of facultative heterochromatin and are required for silencing of developmental genes and maintenance of cell fate1,2,3. Multiple pathways of RNA decay work together to establish and maintain heterochromatin in fission yeast, including a recently identified role for a conserved RNA-degradation complex known as the rixosome or RIX1 complex4,5,6. Whether RNA degradation also has a role in the stability of mammalian heterochromatin remains unknown. Here we show that the rixosome contributes to silencing of many Polycomb targets in human cells. The rixosome associates with human PRC complexes and is enriched at promoters of Polycomb target genes. Depletion of either the rixosome or Polycomb results in accumulation of paused and elongating RNA polymerase at Polycomb target genes. We identify point mutations in the RING1B subunit of PRC1 that disrupt the interaction between PRC1 and the rixosome and result in diminished silencing, suggesting that direct recruitment of the rixosome to chromatin is required for silencing. Finally, we show that the RNA endonuclease and kinase activities of the rixosome and the downstream XRN2 exoribonuclease, which degrades RNAs with 5′ monophosphate groups generated by the rixosome, are required for silencing. Our findings suggest that rixosomal degradation of nascent RNA is conserved from fission yeast to human, with a primary role in RNA degradation at facultative heterochromatin in human cells.

DOI: 10.1038/s41586-022-04598-0

Source: https://www.nature.com/articles/s41586-022-04598-0

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