Basic Sciences Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA 98109, USA.
Basic Sciences Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA 98109, USA; Howard Hughes Medical Institute, USA.
Mol Cell. 2019 Aug 8;75(3):562-575.e5. doi: 10.1016/j.molcel.2019.05.025. Epub 2019 Jun 25.
Although the in vitro structural and in vivo spatial characteristics of transcription factor (TF) binding are well defined, TF interactions with chromatin and other companion TFs during development are poorly understood. To analyze such interactions in vivo, we profiled several TFs across a time course of human embryonic stem cell differentiation and studied their interactions with nucleosomes and co-occurring TFs by enhanced chromatin occupancy (EChO), a computational strategy for classifying TF interactions with chromatin. EChO shows that multiple individual TFs can employ either direct DNA binding or "pioneer" nucleosome binding at different enhancer targets. Nucleosome binding is not exclusively confined to inaccessible chromatin but rather correlated with local binding of other TFs and degeneracy at key bases in the pioneer factor target motif responsible for direct DNA binding. Our strategy reveals a dynamic exchange of TFs at enhancers across developmental time that is aided by pioneer nucleosome binding.
尽管转录因子 (TF) 结合的体外结构和体内空间特征已得到很好的定义，但在发育过程中，TF 与染色质和其他伴随 TF 的相互作用仍知之甚少。为了在体内分析这种相互作用，我们在人类胚胎干细胞分化的时间过程中对几种 TF 进行了分析，并通过增强染色质占有率 (EChO) 研究了它们与核小体和共同发生的 TF 的相互作用，EChO 是一种用于分类 TF 与染色质相互作用的计算策略。EChO 表明，多个单个 TF 可以在不同的增强子靶标上采用直接 DNA 结合或“先驱”核小体结合。核小体结合不仅局限于不可及的染色质，而是与其他 TF 的局部结合以及负责直接 DNA 结合的先驱因子靶标模体中的关键碱基的简并性相关。我们的策略揭示了在发育时间内，增强子上的 TF 之间存在动态交换，这种交换得益于先驱核小体结合的辅助。
