Biochemistry and Molecular Biology Track, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905.
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905.
Proc Natl Acad Sci U S A. 2018 Jul 3;115(27):E6162-E6171. doi: 10.1073/pnas.1801909115. Epub 2018 Jun 18.
Bivalent chromatin domains containing repressive H3K27me3 and active H3K4me3 modifications are barriers for the expression of lineage-specific genes in ES cells and must be resolved for the transcription induction of these genes during differentiation, a process that remains largely unknown. Here, we show that Asf1a, a histone chaperone involved in nucleosome assembly and disassembly, regulates the resolution of bivalent domains and activation of lineage-specific genes during mouse ES cell differentiation. Deletion of Asf1a does not affect the silencing of pluripotent genes, but compromises the expression of lineage-specific genes during ES cell differentiation. Mechanistically, the Asf1a-histone interaction, but not the role of Asf1a in nucleosome assembly, is required for gene transcription. Asf1a is recruited to several bivalent promoters, partially through association with transcription factors, and mediates nucleosome disassembly during differentiation. We suggest that Asf1a-mediated nucleosome disassembly provides a means for resolution of bivalent domain barriers for induction of lineage-specific genes during differentiation.
含有抑制性 H3K27me3 和活性 H3K4me3 修饰的二价染色质域是 ES 细胞中谱系特异性基因表达的障碍，在分化过程中必须解决这些基因的转录诱导问题，而这一过程在很大程度上尚不清楚。在这里，我们表明，参与核小体组装和拆卸的组蛋白伴侣 Asf1a 调节二价结构域的解析和谱系特异性基因在小鼠 ES 细胞分化过程中的激活。Asf1a 的缺失不影响多能基因的沉默，但会损害 ES 细胞分化过程中谱系特异性基因的表达。在机制上，Asf1a 与组蛋白的相互作用，而不是 Asf1a 在核小体组装中的作用，是基因转录所必需的。Asf1a 被招募到几个二价启动子上，部分是通过与转录因子的关联，并且在分化过程中介导核小体的拆卸。我们认为，Asf1a 介导的核小体拆卸为分化过程中诱导谱系特异性基因提供了一种克服二价结构域障碍的方法。
