PT  - JOURNAL ARTICLE
AU  - Gennadi V. Glinsky
TI  - Human-specific genomic features of pluripotency regulatory networks link NANOG with fetal and adult brain development
AID  - 10.1101/022913
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 022913
4099  - http://biorxiv.org/content/early/2017/06/19/022913.short
4100  - http://biorxiv.org/content/early/2017/06/19/022913.full
AB  - 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-HydromethylcytosineCTCF, CCCTC-binding factorDHS, DNase hypersensitivity sitesFHSRR, fixed human-specific regulatory regionsGRNs, genomic regulatory networksHAR, human accelerated regionshCONDEL, human-specific conserved deletionshESC, human embryonic stem cellsHSGRL, human-specific genomic regulatory lociHSNBS, human-specific NANOG-binding sitesHSTFBS, human-specific transcription factor-binding sitesLAD, lamina-associated domainLINE, long interspersed nuclear elementlncRNA, long non-coding RNALTR, long terminal repeatMADE, methylation-associated DNA editingmC, methylcytosinemESC, mouse embryonic stem cellsNANOG, Nanog homeoboxnt, nucleotidePOU5F1, POU class 5 homeobox 1PSDS, partial strand displacement stateTAD, topologically associating domainsTE, transposable elementsTF, transcription factorTSC, triple-stranded complexTSS, transcription start sitesSE, super-enhancersSED, super-enhancer domainssncRNA, small non coding RNA