Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
EMBO J. 2013 Apr 17;32(8):1075-86. doi: 10.1038/emboj.2013.54. Epub 2013 Mar 15.
Histone chaperones affect chromatin structure and gene expression through interaction with histones and RNA polymerase II (PolII). Here, we report that the histone chaperone Spt6 counteracts H3K27me3, an epigenetic mark deposited by the Polycomb Repressive Complex 2 (PRC2) and associated with transcriptional repression. By regulating proper engagement and function of the H3K27 demethylase KDM6A (UTX), Spt6 effectively promotes H3K27 demethylation, muscle gene expression, and cell differentiation. ChIP-Seq experiments reveal an extensive genome-wide overlap of Spt6, PolII, and KDM6A at transcribed regions that are devoid of H3K27me3. Mammalian cells and zebrafish embryos with reduced Spt6 display increased H3K27me3 and diminished expression of the master regulator MyoD, resulting in myogenic differentiation defects. As a confirmation for an antagonistic relationship between Spt6 and H3K27me3, inhibition of PRC2 permits MyoD re-expression in myogenic cells with reduced Spt6. Our data indicate that, through cooperation with PolII and KDM6A, Spt6 orchestrates removal of H3K27me3, thus controlling developmental gene expression and cell differentiation.
组蛋白伴侣通过与组蛋白和 RNA 聚合酶 II（PolII）的相互作用来影响染色质结构和基因表达。在这里，我们报告说组蛋白伴侣 Spt6 可以拮抗 H3K27me3，H3K27me3 是由多梳抑制复合物 2（PRC2）沉积的表观遗传标记，与转录抑制有关。通过调节 H3K27 去甲基酶 KDM6A（UTX）的适当结合和功能，Spt6 有效地促进了 H3K27 的去甲基化、肌肉基因表达和细胞分化。ChIP-Seq 实验揭示了 Spt6、PolII 和 KDM6A 在转录区域的广泛基因组范围内重叠，这些区域缺乏 H3K27me3。Spt6 减少的哺乳动物细胞和斑马鱼胚胎显示出增加的 H3K27me3 和主调控因子 MyoD 的表达减少，导致成肌分化缺陷。作为 Spt6 和 H3K27me3 之间拮抗关系的证实，抑制 PRC2 允许在 Spt6 减少的成肌细胞中重新表达 MyoD。我们的数据表明，Spt6 通过与 PolII 和 KDM6A 的合作，协调 H3K27me3 的去除，从而控制发育基因表达和细胞分化。
