Mechanistic study of mammalian CHD4 in 3D chromatin structure and topology

Abstract

CTCF plays a critical role in maintaining the three-dimensional (3D) chromatin organization, which is important for gene regulation, as it allows distal regulatory elements to come into proximity with one another. However, the detailed mechanism responsible for establishing and maintaining the recruitment of CTCF remains elusive. Here, we use in situ Hi-C to show that the ATP-dependent chromatin remodeler, Chd4, regulates intra-chromatin looping by controlling chromatin accessibility to conceal aberrant CTCF-binding sites in mouse embryonic stem cells (mESCs). These aberrant CTCF-binding sites are embedded in B2 SINEs and are localized within the interior of chromatin loops. In the absence of Chd4, the aberrant CTCF-binding sites become accessible and improper CTCF recruitment occurs, resulting in disorganization of the 3D chromatin architecture and subsequent disruption of enhancer-promoter interactions and the transcription of the corresponding genes. These results indicate that Chd4 regulates adequate transcription of mESCs by securing the proper 3D chromatin organization. These results highlight the Chd4-mediated maintenance of 3D chromatin organization is required for adequate transcription in mESCs.