Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, CNRS UMR5242, Ecole Normale Supérieure de Lyon, F-69007 Lyon, France.
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.
Proc Natl Acad Sci U S A. 2017 Apr 11;114(15):3909-3914. doi: 10.1073/pnas.1614664114. Epub 2017 Mar 27.
Lysine Specific Demethylase 1 (LSD1) removes mono- and dimethyl groups from lysine 4 of histone H3 (H3K4) or H3K9, resulting in repressive or activating (respectively) transcriptional histone marks. The mechanisms that control the balance between these two antagonist activities are not understood. We here show that LSD1 and the orphan nuclear receptor estrogen-related receptor α (ERRα) display commonly activated genes. Transcriptional activation by LSD1 and ERRα involves H3K9 demethylation at the transcriptional start site (TSS). Strikingly, ERRα is sufficient to induce LSD1 to demethylate H3K9 in vitro. The relevance of this mechanism is highlighted by functional data. LSD1 and ERRα coregulate several target genes involved in cell migration, including the MMP1 matrix metallo-protease, also activated through H3K9 demethylation at the TSS. Depletion of LSD1 or ERRα reduces the cellular capacity to invade the extracellular matrix, a phenomenon that is rescued by MMP1 reexpression. Altogether our results identify a regulatory network involving a direct switch in the biochemical activities of a histone demethylase, leading to increased cell invasion.
赖氨酸特异性脱甲基酶 1（LSD1）可从组蛋白 H3 的赖氨酸 4（H3K4）或 H3K9 上去除单甲基和二甲基，导致抑制性或激活性（分别）转录组蛋白标记。控制这两种拮抗活性之间平衡的机制尚不清楚。我们在这里表明，LSD1 和孤儿核受体雌激素相关受体α（ERRα）显示共同激活的基因。LSD1 和 ERRα 的转录激活涉及转录起始位点（TSS）处的 H3K9 去甲基化。令人惊讶的是，ERRα足以诱导 LSD1 在体外对 H3K9 进行去甲基化。该机制的相关性突出表现在功能数据中。LSD1 和 ERRα 共同调节几个参与细胞迁移的靶基因，包括 MMP1 基质金属蛋白酶，该酶也通过 TSS 处的 H3K9 去甲基化激活。LSD1 或 ERRα 的耗竭降低了细胞侵袭细胞外基质的能力，而 MMP1 的重新表达可挽救这一现象。总之，我们的研究结果确定了一个涉及组蛋白去甲基酶生化活性直接转换的调控网络，导致细胞侵袭增加。
