Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Cell. 2021 Dec 9;184(25):6174-6192.e32. doi: 10.1016/j.cell.2021.10.022. Epub 2021 Nov 4.
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 larger number of X-linked genes is unknown. We show that Xist foci are locally confined, contain ∼2 RNA molecules, and nucleate supramolecular complexes (SMACs) that include many copies of the critical silencing protein SPEN. Aggregation and exchange of SMAC proteins generate local protein gradients that regulate broad, proximal chromatin regions. Partitioning of numerous SPEN molecules into SMACs is mediated by their intrinsically disordered regions and essential for transcriptional repression. Polycomb deposition via SMACs induces chromatin compaction and the increase in SMACs density around genes, which propagates silencing across the X chromosome. Our findings introduce a mechanism for functional nuclear compartmentalization whereby crowding of transcriptional and architectural regulators enables the silencing of many target genes by few RNA molecules.
长链非编码 RNA Xist 形成约 50 个衍射限制焦点,以转录沉默一条 X 染色体。这个数量相对较少的 RNA 焦点和相互作用的蛋白质如何调节数量更多的 X 连锁基因尚不清楚。我们发现 Xist 焦点是局部受限的,包含约 2 个 RNA 分子,并形成包含许多关键沉默蛋白 SPEN 的超分子复合物 (SMACs)。SMAC 蛋白的聚集和交换产生了局部的蛋白质梯度,从而调节广泛的近端染色质区域。许多 SPEN 分子被分配到 SMACs 中,这是由它们固有的无序区域介导的,对于转录抑制是必需的。通过 SMACs 进行多梳蛋白沉积会诱导染色质紧缩,并增加基因周围 SMACs 的密度,从而在整个 X 染色体上传播沉默。我们的发现引入了一种功能性核区室化的机制,其中转录和结构调节剂的拥挤使得少数 RNA 分子能够沉默许多靶基因。