Ludwig Institute for Cancer Research, La Jolla, CA, USA.
Aptose Biosciences, Inc., San Diego, CA, USA.
Nat Genet. 2018 Jan;50(1):73-82. doi: 10.1038/s41588-017-0015-6. Epub 2017 Dec 18.
Enhancers act to regulate cell-type-specific gene expression by facilitating the transcription of target genes. In mammalian cells, active or primed enhancers are commonly marked by monomethylation of histone H3 at lysine 4 (H3K4me1) in a cell-type-specific manner. Whether and how this histone modification regulates enhancer-dependent transcription programs in mammals is unclear. In this study, we conducted SILAC mass spectrometry experiments with mononucleosomes and identified multiple H3K4me1-associated proteins, including many involved in chromatin remodeling. We demonstrate that H3K4me1 augments association of the chromatin-remodeling complex BAF to enhancers in vivo and that, in vitro, H3K4me1-marked nucleosomes are more efficiently remodeled by the BAF complex. Crystal structures of the BAF component BAF45C indicate that monomethylation, but not trimethylation, is accommodated by BAF45C's H3K4-binding site. Our results suggest that H3K4me1 has an active role at enhancers by facilitating binding of the BAF complex and possibly other chromatin regulators.
增强子通过促进靶基因的转录来调节细胞类型特异性基因表达。在哺乳动物细胞中，活性或启动的增强子通常以细胞类型特异性的方式被组蛋白 H3 赖氨酸 4（H3K4me1）的单甲基化标记。这种组蛋白修饰是否以及如何调节哺乳动物中增强子依赖的转录程序尚不清楚。在这项研究中，我们使用单核小体进行了 SILAC 质谱实验，鉴定了多个 H3K4me1 相关蛋白，包括许多参与染色质重塑的蛋白。我们证明 H3K4me1 增强了染色质重塑复合物 BAF 与体内增强子的结合，并且在体外，BAF 复合物更有效地重塑 H3K4me1 标记的核小体。BAF 成分 BAF45C 的晶体结构表明，单甲基化而不是三甲基化被 BAF45C 的 H3K4 结合位点容纳。我们的结果表明，H3K4me1 通过促进 BAF 复合物和可能其他染色质调节剂的结合，在增强子上发挥积极作用。
