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

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.

arXiv admin note: substantial text overlap with arXiv:1507.05368

References in corpus (2)

• Identification and characterization of unique to human regulatory sequences in embryonic stem cells reveal associations with transposable elements, distal enhancers, non-coding RNA, and DNA methylation-driven mechanisms of genome editing
• Phenotypic divergence of Homo sapiens is driven by the evolution of human-specific genomic regulatory networks via two mechanistically distinct pathways of creation of divergent regulatory DNA sequences

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