A mechanistic link between gene regulation and genome architecture in mammalian development

Abstract

The organization of chromatin within the nucleus and the regulation of transcription are tightly linked. Recently, mechanisms underlying this relationship have been uncovered. By defining the organizational hierarchy of the genome, determining changes in chromatin organization associated with changes in cell identity, and describing chromatin organization within the context of linear genomic features (such as chromatin modifications and transcription factor binding) and architectural proteins (including Cohesin, CTCF, and Mediator), a new paradigm in genome biology was established wherein genomes are organized around gene regulatory factors that govern cell identity. As such, chromatin organization plays a central role in establishing and maintaining cell state during development, with gene regulation and genome organization being mutually dependent effectors of cell identity.

Figure 1. Gene regulatory factors shape inter-TAD chromatin interactions within the ESC nucleus

Chromatin within the ESC nucleus is compartmentalized based on the preferential co-localization of open, transcriptionally permissive ‘A’ compartment chromatin (white background away from the nuclear periphery) or closed, nuclear lamina-associated ‘B’ compartment chromatin (gray background, nuclear lamina-associated). Within the ‘A’ compartment, genomic regions enriched for binding by pluripotency transcription factors, Mediator, or Cohesin (purple), co-localize, as do regions enriched for Polycomb proteins and the H3K27me3 histone mark (green). Loss off pluripotency transcription factors, Mediator, or Cohesin, or the Polycomb repressive complex 2 (arrows) result in loss of inter-TAD interactions, without disrupting the overall A vs. B compartmental structure of the nucleus.

Figure 2. Architectural proteins act combinatorially to organize chromatin at different length-scales

A) TAD boundaries are enriched for CTCF and Cohesin, but these proteins can also act in combination with other factors, such as Mediator to partition these large Mb-scale TADs into smaller sub-TADs and to facilitate enhancer-promoter interactions. B) A gene regulatory event involving a constitutive promoter-enhancer interaction. Pre-established Mediator-dependent looping of "anti-pause" enhancers to a target gene promoter is followed by the recruitment of the jumonji C-domain-containing protein 6 (JMJD6) and bromodomain-containing protein 4 (Brd4) complex. Brd4/JMJD6-dependent erasure of H4R3me2 and concomitant decapping/demethylation of 7SK snRNA ensures the release of the 7SK snRNA/HEXIM complex, which inhibits elongation factor P-TEFb, permitting pause release and transcriptional elongation.