Yale University, Department of Molecular, Cellular and Developmental Biology, Faculty of Arts and Sciences, 260 Whitney Avenue, New Haven, CN 06511.
Wellcome Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3BF.
Plant Cell. 2021 May 31;33(4):961-979. doi: 10.1093/plcell/koaa027.
Epigenetic mechanisms play diverse roles in the regulation of genome stability in eukaryotes. In Arabidopsis thaliana, genome stability is maintained during DNA replication by the H3.1K27 methyltransferases ARABIDOPSIS TRITHORAX-RELATED PROTEIN 5 (ATXR5) and ATXR6, which catalyze the deposition of K27me1 on replication-dependent H3.1 variants. The loss of H3.1K27me1 in atxr5 atxr6 double mutants leads to heterochromatin defects, including transcriptional de-repression and genomic instability, but the molecular mechanisms involved remain largely unknown. In this study, we identified the transcriptional co-activator and conserved histone acetyltransferase GCN5 as a mediator of transcriptional de-repression and genomic instability in the absence of H3.1K27me1. GCN5 is part of a SAGA-like complex in plants that requires the GCN5-interacting protein ADA2b and the chromatin remodeler CHR6 to mediate the heterochromatic defects in atxr5 atxr6 mutants. Our results also indicate that Arabidopsis GCN5 acetylates multiple lysine residues on H3.1 variants, but H3.1K27 and H3.1K36 play essential functions in inducing genomic instability in the absence of H3.1K27me1. Finally, we show that H3.1K36 acetylation by GCN5 is negatively regulated by H3.1K27me1 in vitro. Overall, this work reveals a key molecular role for H3.1K27me1 in maintaining transcriptional silencing and genome stability in heterochromatin by restricting GCN5-mediated histone acetylation in plants.
表观遗传机制在真核生物基因组稳定性的调节中发挥着多样化的作用。在拟南芥中，基因组稳定性在 DNA 复制过程中通过 H3.1K27 甲基转移酶 ARABIDOPSIS TRITHORAX-RELATED PROTEIN 5 (ATXR5) 和 ATXR6 得到维持，它们催化复制依赖性 H3.1 变体上 K27me1 的沉积。在 atxr5 atxr6 双突变体中，H3.1K27me1 的缺失导致异染色质缺陷，包括转录去阻遏和基因组不稳定性，但涉及的分子机制在很大程度上仍然未知。在这项研究中，我们鉴定了转录共激活因子和保守的组蛋白乙酰转移酶 GCN5 作为 H3.1K27me1 缺失时转录去阻遏和基因组不稳定性的介导物。GCN5 是植物中 SAGA 样复合物的一部分，该复合物需要 GCN5 相互作用蛋白 ADA2b 和染色质重塑因子 CHR6 来介导 atxr5 atxr6 突变体中的异染色质缺陷。我们的结果还表明，拟南芥 GCN5 乙酰化 H3.1 变体上的多个赖氨酸残基，但 H3.1K27 和 H3.1K36 在 H3.1K27me1 缺失时诱导基因组不稳定性方面发挥着重要作用。最后，我们表明 GCN5 对 H3.1K36 的乙酰化作用在体外受到 H3.1K27me1 的负调控。总的来说，这项工作揭示了 H3.1K27me1 在通过限制植物中 GCN5 介导的组蛋白乙酰化来维持异染色质中转录沉默和基因组稳定性方面的关键分子作用。
