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). In this contribution, the genome-wide proximity placement analysis of human-specific genomic regulatory loci (HSGRL), hESC-enriched enhancers, super-enhancers (SEs), topologically-associating domains (TADS), and specific sub-TAD structures termed super-enhancer domains (SEDs) has been performed. In the hESC genome, 331 of 504 (66%) of SED-harboring TADs contain HSGRL and 68% of SEDs co-localize with HSGRL, suggesting that emergence of HSGRL may have rewired SED-associated GRNs within specific TADs by inserting novel and/or erasing existing non-coding regulatory sequences. Consequently, 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 rates 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 (or a set of functionally-linked genes) per regulatory domain structures.
Footnotes
- List of abbreviations
- 5hmC
- 5-Hydromethylcytosine
- CTCF
- CCCTC-binding factor
- DHS
- DNase hypersensitivity sites
- FHSRR
- fixed human-specific regulatory regions
- GRNs
- genomic regulatory networks
- HAR
- human accelerated regions
- hCONDEL
- human-specific conserved deletions
- hESC
- human embryonic stem cells
- HSGRL
- human-specific genomic regulatory loci
- HSNBS
- human-specific NANOG-binding sites
- HSTFBS
- human-specific transcription factor-binding sites
- LAD
- lamina-associated domain
- LINE
- long interspersed nuclear element
- lncRNA
- long non-coding RNA
- LTR
- long terminal repeat
- MADE
- methylation-associated DNA editing
- mC
- methylcytosine
- mESC
- mouse embryonic stem cells
- NANOG
- Nanog homeobox
- nt
- nucleotide
- POU5F1
- POU class 5 homeobox 1
- TAD
- topologically associating domains
- TE
- transposable elements
- TF
- transcription factor
- SE
- super-enhancers
- SED
- super-enhancer domains