美国加州大学Kathrin Plath、Yolanda Markaki研究团队的研究发现Xist通过介导局部蛋白质梯度成核沉默X染色体。相关论文于2021年11月4日发表在《细胞》杂志上。

研究人员发现Xist聚集是位点特异的，包含~2个RNA分子，并介导超分子复合物(SMAC)成核，其中包括多拷贝的关键沉默蛋白SPEN。SMAC蛋白的聚集和交换产生局部蛋白梯度，调节广泛的近端染色质区域。将大量SPEN分子分配到SMAC中是由其固有无序区域介导的，并且对转录抑制至关重要。

通过SMAC的多梳沉积诱导染色质压实和增加基因周围SMAC的密度，从而逐步介导X染色体沉默。该研究揭示了一种功能性核区室化机制，其中转录和结构调节因子的聚集使许多靶基因可被很少量的RNA所沉默。

研究人员表示，lncRNA Xist通过形成约50个衍射限制位点来转录沉默X染色体。尚不清楚这些少量的RNA集合与其相互作用的蛋白如何调节大量的X连锁基因。

附：英文原文

Title: Xist nucleates local protein gradients to propagate silencing across the X chromosome

Author: Yolanda Markaki, Johnny Gan Chong, Yuying Wang, Elsie C. Jacobson, Christy Luong, Shawn Y.X. Tan, Davide Maestrini, Abhik K. Banerjee, Bhaven A. Mistry, Iris Dror, Francois Dossin, Johannes Schneberg, Edith Heard, Mitchell Guttman, Tom Chou, Kathrin Plath

Issue&Volume: 2021-11-04

Abstract: The lncRNA Xist forms ～50 diffraction-limited foci to transcriptionally silence one X chromosome.How this small number of RNA foci and interacting proteins regulate a much largernumber of X-linked genes is unknown. We show that Xist foci are locally confined, contain ～2 RNA molecules, and nucleate supramolecularcomplexes (SMACs) that include many copies of the critical silencing protein SPEN.Aggregation and exchange of SMAC proteins generate local protein gradients that regulatebroad, proximal chromatin regions. Partitioning of numerous SPEN molecules into SMACsis mediated by their intrinsically disordered regions and essential for transcriptionalrepression. Polycomb deposition via SMACs induces chromatin compaction and the increasein SMACs density around genes, which propagates silencing across the X chromosome.Our findings introduce a mechanism for functional nuclear compartmentalization wherebycrowding of transcriptional and architectural regulators enables the silencing ofmany target genes by few RNA molecules.

DOI: 10.1016/j.cell.2021.10.022

Source: https://www.cell.com/cell/fulltext/S0092-8674(21)01275-7