Harada Akihito, Maehara Kazumitsu, Sato Yuko, Konno Daijiro, Tachibana Taro, Kimura Hiroshi, Ohkawa Yasuyuki
Department of Advanced Medical Initiatives, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan.
Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, 226-8501, Japan CREST, JST, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0021, Japan.
Nucleic Acids Res. 2015 Jan;43(2):775-86. doi: 10.1093/nar/gku1346. Epub 2014 Dec 24.
Lineage potential is triggered by lineage-specific transcription factors in association with changes in the chromatin structure. Histone H3.3 variant is thought to play an important role in the regulation of lineage-specific genes. To elucidate the function of H3.3 in myogenic differentiation, we forced the expression of GFP-H3.1 to alter the balance between H3.1 and H3.3 in mouse C2C12 cells that could be differentiated into myotubes. GFP-H3.1 replaced H3.3 in the regulatory regions of skeletal muscle (SKM) genes and induced a decrease of H3K4 trimethylation (H3K4me3) and increase of H3K27 trimethylation (H3K27me3). Similar results were obtained by H3.3 knockdown. In contrast, MyoD-dependent H3.3 incorporation into SKM genes in fibroblasts induced an increase of H3K4me3 and H3K27me3. In mouse embryos, a bivalent modification of H3K4me3 and H3K27me3 was formed on H3.3-incorporated SKM genes before embryonic skeletal muscle differentiation. These results suggest that lineage potential is established through a selective incorporation of specific H3 variants that governs the balance of histone modifications.
谱系潜能由谱系特异性转录因子与染色质结构变化共同触发。组蛋白H3.3变体被认为在谱系特异性基因的调控中起重要作用。为了阐明H3.3在肌源性分化中的功能，我们在可分化为肌管的小鼠C2C12细胞中强制表达GFP-H3.1，以改变H3.1和H3.3之间的平衡。GFP-H3.1取代了骨骼肌（SKM）基因调控区域中的H3.3，并导致H3K4三甲基化（H3K4me3）减少和H3K27三甲基化（H3K27me3）增加。通过敲低H3.3也获得了类似的结果。相反，成纤维细胞中MyoD依赖的H3.3掺入SKM基因会导致H3K4me3和H H3K27me3增加。在小鼠胚胎中，在胚胎骨骼肌分化之前，H3.3掺入的SKM基因上形成了H3K4me3和H3K27me3的二价修饰。这些结果表明，谱系潜能是通过特定H3变体的选择性掺入来建立的，这种掺入控制着组蛋白修饰的平衡。
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