Center for Comparative Genomics and Bioinformatics, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Genome Res. 2011 Oct;21(10):1659-71. doi: 10.1101/gr.125088.111. Epub 2011 Jul 27.
Interplays among lineage-specific nuclear proteins, chromatin modifying enzymes, and the basal transcription machinery govern cellular differentiation, but their dynamics of action and coordination with transcriptional control are not fully understood. Alterations in chromatin structure appear to establish a permissive state for gene activation at some loci, but they play an integral role in activation at other loci. To determine the predominant roles of chromatin states and factor occupancy in directing gene regulation during differentiation, we mapped chromatin accessibility, histone modifications, and nuclear factor occupancy genome-wide during mouse erythroid differentiation dependent on the master regulatory transcription factor GATA1. Notably, despite extensive changes in gene expression, the chromatin state profiles (proportions of a gene in a chromatin state dominated by activating or repressive histone modifications) and accessibility remain largely unchanged during GATA1-induced erythroid differentiation. In contrast, gene induction and repression are strongly associated with changes in patterns of transcription factor occupancy. Our results indicate that during erythroid differentiation, the broad features of chromatin states are established at the stage of lineage commitment, largely independently of GATA1. These determine permissiveness for expression, with subsequent induction or repression mediated by distinctive combinations of transcription factors.
谱系特异性核蛋白、染色质修饰酶和基础转录机制之间的相互作用控制着细胞分化，但它们的作用动力学及其与转录调控的协调关系尚未完全明了。染色质结构的改变似乎在某些基因座上为基因激活建立了一个许可状态，但它们在其他基因座上的激活中起着不可或缺的作用。为了确定染色质状态和因子占据在指导分化过程中基因调控方面的主要作用，我们在依赖于主调控转录因子 GATA1 的情况下，在小鼠红细胞分化过程中，对染色质可及性、组蛋白修饰和核因子占据进行了全基因组映射。值得注意的是，尽管基因表达发生了广泛变化，但在 GATA1 诱导的红细胞分化过程中，染色质状态谱（由激活或抑制组蛋白修饰主导的基因的比例）和可及性在很大程度上保持不变。相比之下，基因的诱导和抑制与转录因子占据模式的变化密切相关。我们的结果表明，在红细胞分化过程中，染色质状态的广泛特征在谱系决定阶段就已经建立，这在很大程度上独立于 GATA1。这些特征决定了表达的许可性，随后通过独特的转录因子组合进行诱导或抑制。
