Epigenetic modifications on chromatin play important roles in regulating gene expression. Although chromatin states are often governed by multilayered structure, how individual pathways contribute to gene expression remains poorly understood. For example, DNA methylation is known to regulate transcription factor binding but also to recruit methyl-CpG binding proteins that affect chromatin structure through the activity of histone deacetylase complexes (HDACs). Both of these mechanisms can potentially affect gene expression, but the importance of each, and whether these activities are integrated to achieve appropriate gene regulation, remains largely unknown. To address this important question, we measured gene expression, chromatin accessibility, and transcription factor occupancy in wild-type or DNA methylation-deficient mouse embryonic stem cells following HDAC inhibition. We observe widespread increases in chromatin accessibility at retrotransposons when HDACs are inhibited, and this is magnified when cells also lack DNA methylation. A subset of these elements has elevated binding of the YY1 and GABPA transcription factors and increased expression. The pronounced additive effect of HDAC inhibition in DNA methylation–deficient cells demonstrates that DNA methylation and histone deacetylation act largely independently to suppress transcription factor binding and gene expression.

中文翻译：

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DNA 甲基化和组蛋白乙酰化对转录因子基因组占有率的不同贡献。

染色质上的表观遗传修饰在调节基因表达中起重要作用。尽管染色质状态通常由多层结构控制，但个体途径如何促进基因表达仍知之甚少。例如，已知 DNA 甲基化可调节转录因子结合，但也可通过组蛋白脱乙酰酶复合物 (HDAC) 的活性募集影响染色质结构的甲基-CpG 结合蛋白。这两种机制都可能影响基因表达，但每种机制的重要性，以及这些活动是否被整合以实现适当的基因调控，在很大程度上仍然未知。为了解决这个重要问题，我们测量了基因表达、染色质可及性、HDAC 抑制后野生型或 DNA 甲基化缺陷的小鼠胚胎干细胞中的转录因子占有率。我们观察到当 HDAC 被抑制时，逆转录转座子的染色质可及性普遍增加，当细胞也缺乏 DNA 甲基化时，这种情况会被放大。这些元件的一个子集提高了 YY1 和 GABPA 转录因子的结合并增加了表达。HDAC 抑制在 DNA 甲基化缺陷细胞中的显着累加效应表明 DNA 甲基化和组蛋白去乙酰化在很大程度上独立地抑制转录因子结合和基因表达。这些元件的一个子集提高了 YY1 和 GABPA 转录因子的结合并增加了表达。HDAC 抑制在 DNA 甲基化缺陷细胞中的显着累加效应表明 DNA 甲基化和组蛋白去乙酰化在很大程度上独立地抑制转录因子结合和基因表达。这些元件的一个子集提高了 YY1 和 GABPA 转录因子的结合并增加了表达。HDAC 抑制在 DNA 甲基化缺陷细胞中的显着累加效应表明 DNA 甲基化和组蛋白去乙酰化在很大程度上独立地抑制转录因子结合和基因表达。