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Human-specific genomic features of pluripotency regulatory networks link NANOG with fetal and adult brain development

Gennadi V. Glinsky
doi: https://doi.org/10.1101/022913
Gennadi V. Glinsky
1Institute of Engineering in Medicine, University of California, San Diego, 9500 Gilman Dr. MC 0435, La Jolla, CA 92093-0435, USA
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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

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted June 19, 2017.
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Human-specific genomic features of pluripotency regulatory networks link NANOG with fetal and adult brain development
Gennadi V. Glinsky
bioRxiv 022913; doi: https://doi.org/10.1101/022913
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Human-specific genomic features of pluripotency regulatory networks link NANOG with fetal and adult brain development
Gennadi V. Glinsky
bioRxiv 022913; doi: https://doi.org/10.1101/022913

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