Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Brain and Lung Epigenetics (BLUE), Creteil, France.
Lung Cancer Epigenetic, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
Nat Commun. 2021 Feb 16;12(1):1072. doi: 10.1038/s41467-021-21227-y.
In addition to nucleosomes, chromatin contains non-histone chromatin-associated proteins, of which the high-mobility group proteins are the most abundant. Chromatin-mediated regulation of transcription involves DNA methylation and histone modifications. However, the order of events and the precise function of high-mobility group proteins during transcription initiation remain unclear. Here we show that high-mobility group AT-hook 2 protein (HMGA2) induces DNA nicks at the transcription start site, which are required by the histone chaperone FACT complex to incorporate nucleosomes containing the histone variant H2A.X. Further, phosphorylation of H2A.X at S139 (γ-H2AX) is required for repair-mediated DNA demethylation and transcription activation. The relevance of these findings is demonstrated within the context of TGFB1 signaling and idiopathic pulmonary fibrosis, suggesting therapies against this lethal disease. Our data support the concept that chromatin opening during transcriptional initiation involves intermediates with DNA breaks that subsequently require DNA repair mechanisms to ensure genome integrity.
除核小体外，染色质还包含非组蛋白染色质相关蛋白，其中高迁移率族蛋白最为丰富。染色质介导的转录调控涉及 DNA 甲基化和组蛋白修饰。然而，在转录起始过程中事件的顺序和高迁移率族蛋白的确切功能仍不清楚。在这里，我们发现高迁移率族 AT 钩 2 蛋白（HMGA2）在转录起始位点诱导 DNA 缺口，组蛋白伴侣 FACT 复合物需要这些缺口来掺入含有组蛋白变体 H2A.X 的核小体。此外，H2A.X 在 S139 位点（γ-H2AX）的磷酸化对于修复介导的 DNA 去甲基化和转录激活是必需的。在 TGFB1 信号和特发性肺纤维化的背景下，这些发现的相关性得到了证明，提示针对这种致命疾病的治疗方法。我们的数据支持这样一种概念，即在转录起始过程中染色质的打开涉及具有 DNA 断裂的中间体，随后需要 DNA 修复机制来确保基因组完整性。
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