Physiological Chemistry, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-University Munich, 82152 Planegg-Martinsried, Germany.
Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA; George Williams Hooper Research Foundation, University of California, San Francisco, CA 94143, USA; TETRAD Graduate Program, University of California, San Francisco, CA 94143, USA.
Cell Rep. 2021 Nov 2;37(5):109944. doi: 10.1016/j.celrep.2021.109944.
Heterochromatin formation requires three distinct steps: nucleation, self-propagation (spreading) along the chromosome, and faithful maintenance after each replication cycle. Impeding any of those steps induces heterochromatin defects and improper gene expression. The essential histone chaperone FACT (facilitates chromatin transcription) has been implicated in heterochromatin silencing, but the mechanisms by which FACT engages in this process remain opaque. Here, we pinpoint its function to the heterochromatin spreading process in fission yeast. FACT impairment reduces nucleation-distal H3K9me3 and HP1/Swi6 accumulation at subtelomeres and derepresses genes in the vicinity of heterochromatin boundaries. FACT promotes spreading by repressing heterochromatic histone turnover, which is crucial for the H3K9me2 to me3 transition that enables spreading. FACT mutant spreading defects are suppressed by removal of the H3K9 methylation antagonist Epe1. Together, our study identifies FACT as a histone chaperone that promotes heterochromatin spreading and lends support to the model that regulated histone turnover controls the propagation of repressive methylation marks.
核形成、沿着染色体自我扩展（扩散）以及在每个复制周期后的忠实维持。任何一个步骤的阻碍都会导致异染色质缺陷和不当的基因表达。必需的组蛋白伴侣 FACT（促进染色质转录）已被牵连到异染色质沉默中，但 FACT 参与该过程的机制仍然不清楚。在这里，我们确定了它在裂殖酵母中的异染色质扩展过程中的功能。FACT 功能缺失会减少核形成远端的 H3K9me3 和 HP1/Swi6 在端粒附近的积累，并使异染色质边界附近的基因去抑制。FACT 通过抑制异染色质组蛋白周转来促进扩散，这对于 H3K9me2 到 me3 的转变至关重要，该转变使扩散成为可能。去除 H3K9 甲基化拮抗剂 Epe1 可以抑制 FACT 突变体的扩散缺陷。总的来说，我们的研究确定了 FACT 作为一种组蛋白伴侣，它可以促进异染色质的扩展，并支持调节组蛋白周转控制抑制性甲基化标记传播的模型。
