Functional interplay between MyoD and CTCF in regulating long-range chromatin interactions during differentiation

Abstract

Higher-order chromatin structures appear to be dynamically arranged during development and differentiation. However, the molecular mechanism underlying their maintenance or disruption and their functional relevance to gene regulation are poorly understood. We recently described a dynamic long-range chromatin interaction between the gene promoter of the cdk inhibitor p57(kip2) (also known as Cdkn1c) and the imprinting control region KvDMR1 in muscle cells. Here, we show that CTCF, the best characterized organizer of long-range chromatin interactions, binds to both the p57(kip2) promoter and KvDMR1 and is necessary for the maintenance of their physical contact. Moreover, we show that CTCF-mediated looping is required to prevent p57(kip2) expression before differentiation. Finally, we provide evidence that the induction of p57(kip2) during myogenesis involves the physical interaction of the muscle-regulatory factor MyoD with CTCF at KvDMR1, the displacement of the cohesin complex subunit Rad21 and the destabilization of the chromatin loop. The finding that MyoD affects chromatin looping at CTCF-binding sites represents the first evidence that a differentiation factor regulates chromatin-loop dynamics and provides a useful paradigm for gaining insights into the developmental regulation of long-range chromatin contacts.