1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Nature. 2015 Feb 19;518(7539):344-9. doi: 10.1038/nature14233.
Pluripotent stem cells provide a powerful system to dissect the underlying molecular dynamics that regulate cell fate changes during mammalian development. Here we report the integrative analysis of genome-wide binding data for 38 transcription factors with extensive epigenome and transcriptional data across the differentiation of human embryonic stem cells to the three germ layers. We describe core regulatory dynamics and show the lineage-specific behaviour of selected factors. In addition to the orchestrated remodelling of the chromatin landscape, we find that the binding of several transcription factors is strongly associated with specific loss of DNA methylation in one germ layer, and in many cases a reciprocal gain in the other layers. Taken together, our work shows context-dependent rewiring of transcription factor binding, downstream signalling effectors, and the epigenome during human embryonic stem cell differentiation.
多能干细胞为剖析调控哺乳动物发育过程中细胞命运转变的基础分子动态提供了强有力的系统。在这里，我们报告了对 38 种转录因子的全基因组结合数据进行的综合分析，这些转录因子的广泛表观基因组和转录组数据覆盖了人类胚胎干细胞向三个胚层分化的过程。我们描述了核心调控动态，并展示了选定因子的谱系特异性行为。除了染色质景观的协调重塑之外，我们还发现，几个转录因子的结合与一个胚层中特定的 DNA 甲基化丧失密切相关，在许多情况下，另两个胚层中则会出现相应的获得。总之，我们的工作表明，在人类胚胎干细胞分化过程中，转录因子结合、下游信号效应器和表观基因组的改变具有上下文相关性。
