Department of Chemistry and Molecular Biology, University of Gothenburg, Medicinaregatan, Goteborg, Sweden.
Institute of Biomedicine, University of Gothenburg, Goteborg, Sweden.
PLoS Genet. 2020 May 29;16(5):e1008798. doi: 10.1371/journal.pgen.1008798. eCollection 2020 May.
Alterations in epigenetic silencing have been associated with ageing and tumour formation. Although substantial efforts have been made towards understanding the mechanisms of gene silencing, novel regulators in this process remain to be identified. To systematically search for components governing epigenetic silencing, we developed a genome-wide silencing screen for yeast (Saccharomyces cerevisiae) silent mating type locus HMR. Unexpectedly, the screen identified the mismatch repair (MMR) components Pms1, Mlh1, and Msh2 as being required for silencing at this locus. We further found that the identified genes were also required for proper silencing in telomeres. More intriguingly, the MMR mutants caused a redistribution of Sir2 deacetylase, from silent mating type loci and telomeres to rDNA regions. As a consequence, acetylation levels at histone positions H3K14, H3K56, and H4K16 were increased at silent mating type loci and telomeres but were decreased in rDNA regions. Moreover, knockdown of MMR components in human HEK293T cells increased subtelomeric DUX4 gene expression. Our work reveals that MMR components are required for stable inheritance of gene silencing patterns and establishes a link between the MMR machinery and the control of epigenetic silencing.
表观遗传沉默的改变与衰老和肿瘤形成有关。尽管人们已经做出了巨大的努力来理解基因沉默的机制，但这一过程中的新调节因子仍有待发现。为了系统地寻找控制表观遗传沉默的成分，我们开发了一种针对酵母（酿酒酵母）沉默交配型位点 HMR 的全基因组沉默筛选。出乎意料的是，该筛选发现错配修复（MMR）组件 Pms1、Mlh1 和 Msh2 是该位点沉默所必需的。我们进一步发现，鉴定出的基因也需要在端粒中进行适当的沉默。更有趣的是，MMR 突变体导致 Sir2 脱乙酰酶从沉默交配型位点和端粒重新分布到 rDNA 区域。结果，在沉默交配型位点和端粒处的组蛋白位置 H3K14、H3K56 和 H4K16 的乙酰化水平增加，但在 rDNA 区域则降低。此外，在人 HEK293T 细胞中敲低 MMR 组件会增加亚端粒 DUX4 基因的表达。我们的工作揭示了 MMR 组件对于基因沉默模式的稳定遗传是必需的，并在 MMR 机制和表观遗传沉默的控制之间建立了联系。
