Abstract
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 termed rapidly-evolving in humans TADs (revTADs; Genome Biol Evol. 2016 8; 2774-88). Here, human-specific genomic features of pluripotency regulatory networks in hESC have been analyzed. The primary focus was on identification of human-specific elements of the interphase chromatin architecture of TADs responsible for transcriptional regulatory control of the NANOG, POU5F1, and POU3F2 genes. Comparative analyses of the four adjacent TADs spanning ~3.3 Mb NANOG locus-associated genomic region were carried-out to highlight primate-specific genomic features. Lastly, the putative mechanisms of the genome-wide regulatory effects of human-specific NANOG-binding sites (HSNBS) on expression of genes implicated in the fetal and adult brain development have been examined. Acquisition of primate-specific regulatory loci appears to rewire TADs exerting transcriptional control on pluripotency regulators, revealing a genomic placement pattern consistent with the enhanced regulatory impact of NANOG in primates. Proximity placement analysis of HSNBS identified a large expression signature in the human fetal neocortex temporal lobe comprising 4,957 genes, which appear to retain acquired in the embryo expression changes for many years of human brain development and maintain highly concordant expression profiles in the neocortex and prefrontal cortex regions of adult human brain. Collectively, reported herein observations indicate that genomic elements of pluripotency regulatory circuitry associated with HSNBS, specifically proteins of the classical NurD chromatin remodeling complex, contribute to transcriptional regulation of a large set of genes implicated in development and function of human brain.
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
PSDS, partial strand displacement state
TAD, topologically associating domains
TE, transposable elements
TF, transcription factor
TSC, triple-stranded complex
TSS, transcription start sites
SE, super-enhancers
SED, super-enhancer domains
sncRNA, small non coding RNA
