NuRD-enabled CTCF-TET crosstalk orchestrates epigenome reprogramming and genome architecture.

CCCTC-binding factor (CTCF) is an evolutionarily conserved transcription factor with diverse regulatory roles. Its binding sites exhibit highly ordered nucleosomes and DNA hypomethylation, but how this epigenetic landscape is established remains unclear. In this study, we develop a GpC methylation-assisted tracing (G-MAT) approach to investigate the interplay between DNA methylation and CTCF binding at a base-pair resolution, which reveals that CTCF-chromatin interaction frequently coincides with methylated DNA, which is likely mediated by the nucleosome remodeling and deacetylase (NuRD) complex. We show that NuRD is indispensable for CTCF's chromatin binding, emerging as a regulator of high-order genome architecture. Mechanistically, NuRD facilitates CTCF to interact with TET methylcytosine dioxygenase to maintain adjacent DNA hypomethylation, which is essential for activation of nearby genes. Notably, embryonic stem cells lacking NuRD exhibit impaired lineage commitment. Together, our study unravels a mechanism that elucidates the crosstalk between CTCF binding and the epigenome, with NuRD playing a crucial role as a mediator.