Role of distal enhancers in shaping 3D-folding patterns and defining human-specific features of interphase chromatin architecture in embryonic stem cells

TL;DR

This study investigates how human-specific distal enhancers influence 3D chromatin architecture in embryonic stem cells, revealing increased regulatory domain complexity and potential mechanisms for human-specific gene regulation.

Contribution

It provides a comprehensive analysis of human-specific enhancers and super-enhancer domains, highlighting their role in shaping 3D chromatin folding unique to human embryonic stem cells.

Findings

Increased number and size of super-enhancer domains in human ESCs

Higher quantity and smaller size of TADs in human ESCs compared to mouse

Evidence for human-specific 3D chromatin folding patterns

Abstract

Molecular and genetic definitions of human-specific changes to genomic regulatory networks (GRNs) contributing to development of unique to human phenotypes remain a highly significant challenge. Genome-wide proximity placement analysis of diverse families of human-specific genomic regulatory loci (HSGRL) identified topologically-associating domains (TADs) that are significantly enriched for HSGRL and designated rapidly-evolving in humans TADs (Genome Biol Evol. 2016 8; 2774-88). Here, the analysis of HSGRL, hESC-enriched enhancers, super-enhancers (SEs), and specific sub-TAD structures termed super-enhancer domains (SEDs) has been performed. Markedly distinct features of the principal regulatory structures of interphase chromatin evolved in the hESC genome compared to mouse: the SED quantity is 3-fold higher and the median SED size is significantly larger. Concomitantly, the overall TAD quantity is increased by 42% while the median TAD size is significantly decreased (p = 9.11E-37) in the hESC genome. Present analyses illustrate a putative global role for HSGRL in shaping the human-specific features of the interphase chromatin organization and functions, which are facilitated by accelerated creation of new enhancers associated with targeted placement of HSGRL at defined genomic coordinates. A trend toward the convergence of TAD and SED architectures of interphase chromatin in the hESC genome may reflect changes of 3D-folding patterns of linear chromatin fibers designed to enhance both regulatory complexity and functional precision of GRNs by creating predominantly a single gene per regulatory domain structures.