Department of Pathology and Perlmutter Cancer Institute, New York University School of Medicine, New York, NY, 10016, USA.
CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
Nat Commun. 2020 Dec 4;11(1):6222. doi: 10.1038/s41467-020-19999-w.
Using Hi-C, promoter-capture Hi-C (pCHi-C), and other genome-wide approaches in skeletal muscle progenitors that inducibly express a master transcription factor, Pax7, we systematically characterize at high-resolution the spatio-temporal re-organization of compartments and promoter-anchored interactions as a consequence of myogenic commitment and differentiation. We identify key promoter-enhancer interaction motifs, namely, cliques and networks, and interactions that are dependent on Pax7 binding. Remarkably, Pax7 binds to a majority of super-enhancers, and together with a cadre of interacting transcription factors, assembles feed-forward regulatory loops. During differentiation, epigenetic memory and persistent looping are maintained at a subset of Pax7 enhancers in the absence of Pax7. We also identify and functionally validate a previously uncharacterized Pax7-bound enhancer hub that regulates the essential myosin heavy chain cluster during skeletal muscle cell differentiation. Our studies lay the groundwork for understanding the role of Pax7 in orchestrating changes in the three-dimensional chromatin conformation in muscle progenitors.
利用 Hi-C、启动子捕获 Hi-C（pCHi-C）和其他在诱导表达主转录因子 Pax7 的骨骼肌祖细胞中的全基因组方法，我们系统地描述了肌生成和分化过程中隔室和启动子锚定相互作用的时空重组织。我们确定了关键的启动子增强子相互作用基序，即团簇和网络，以及依赖于 Pax7 结合的相互作用。值得注意的是，Pax7 结合到大多数超级增强子上，并与一组相互作用的转录因子一起组装前馈调节回路。在分化过程中，在没有 Pax7 的情况下，一小部分 Pax7 增强子中的表观遗传记忆和持续的环化得以维持。我们还鉴定并功能验证了一个以前未被描述的 Pax7 结合增强子枢纽，它在骨骼肌细胞分化过程中调节必需的肌球蛋白重链簇。我们的研究为理解 Pax7 在协调肌肉祖细胞中三维染色质构象变化中的作用奠定了基础。
