PT - JOURNAL ARTICLE AU - Gennadi V. Glinsky TI - Remodeling of the interphase chromatin domain structures in embryonic stem cells by targeted placement of human-specific regulatory loci AID - 10.1101/022913 DP - 2015 Jan 01 TA - bioRxiv PG - 022913 4099 - http://biorxiv.org/content/early/2015/07/21/022913.short 4100 - http://biorxiv.org/content/early/2015/07/21/022913.full AB - Thousands of candidate human-specific genomic regulatory loci (HSGRL) have been identified, supporting the idea that unique to human phenotypes result from human-specific changes to genomic regulatory networks (GRNs). A notable common feature of HSGRL is a predominant location within non-protein coding sequences. A significant void is the lack of a genome-wide view on diverse families of HSGRL within the context of the principal regulatory structures of the interphase chromatin, namely topologically-associating domains (TADs) and specific sub-TAD structures termed super-enhancer domains (SEDs). Genome-wide proximity placement analysis of 10,598 HSGRL revealed that 0.8%-10.3% of TADs contain more than half of HSGRL. Of the 3,127 TADs in the hESC genome, 24 (0.8%); 53 (1.7%); 259 (8.3%); and 322 (10.3%) harbor 1,110 (52.4%); 1,936 (50.9%); 1,151 (59.6%); and 1,601 (58.3%) HSGRL sequences from four distinct families, respectively. TADs that are enriched for HSGRL and termed rapidly-evolving in humans TADs (revTADs) manifest distinct correlation patterns between HSGRL placements and recombination rates. There are significant enrichment within revTAD boundaries of hESC-enhancers, primate-specific CTCF-binding sites, human-specific RNAPII-binding sites, hCONDELs, and H3K4me3 peaks with human-specific enrichment at TSS in prefrontal cortex neurons (p < 0.0001 in all instances). In hESC genome, 331 of 504 (66%) of SE-harboring TADs contain HSGRL and 68% of SEs co-localize with HSGRL, suggesting that HSGRL rewired SE-driven GRNs within revTADs by inserting novel and/or erasing existing regulatory sequences. Consequently, markedly distinct features of chromatin structures evolved in hESC compared to mouse: the SE quantity is 3-fold higher and the median SE size is significantly larger; concomitantly, the TAD number is increased by 42% while the median TAD size is decreased (p=9.11E-37). Present analyses revealed a global role for HSGRL in increasing both quantity and size of SEs and increasing the number and size reduction of TADs, which may facilitate a convergence of TAD and SED architectures of interphase chromatin and define a trend of increasing regulatory complexity during evolution of GRNs.List of abbreviations5hmC5-HydromethylcytosineCTCFCCCTC-binding factorDHSDNase hypersensitivity sitesFHSRRfixed human-specific regulatory regionsGRNsgenomic regulatory networksHARhuman accelerated regionshCONDELhuman-specific conserved deletionshESChuman embryonic stem cellsHSGRLhuman-specific genomic regulatory lociHSNBShuman-specific NANOG-binding sitesHSTFBShuman-specific transcription factor-binding sitesLADlamina-associated domainLINElong interspersed nuclear elementlncRNAlong non-coding RNALTRlong terminal repeatMADEmethylation-associated DNA editingmCmethylcytosinemESCmouse embryonic stem cellsNANOGNanog homeoboxntnucleotidePOU5F1POU class 5 homeobox 1PSDSpartial strand displacement stateTADtopologically associating domainsTEtransposable elementsTFtranscription factorTSCtriple-stranded complexTSStranscription start sitesSEsuper-enhancersSEDsuper-enhancer domainssncRNAsmall non coding RNAList of abbreviations5hmC5-HydromethylcytosineCTCFCCCTC-binding factorDHSDNase hypersensitivity sitesFHSRRfixed human-specific regulatory regionsGRNsgenomic regulatory networksHARhuman accelerated regionshCONDELhuman-specific conserved deletionshESChuman embryonic stem cellsHSGRLhuman-specific genomic regulatory lociHSNBShuman-specific NANOG-binding sitesHSTFBShuman-specific transcription factor-binding sitesLADlamina-associated domainLINElong interspersed nuclear elementlncRNAlong non-coding RNALTRlong terminal repeatMADEmethylation-associated DNA editingmCmethylcytosinemESCmouse embryonic stem cellsNANOGNanog homeoboxntnucleotidePOU5F1POU class 5 homeobox 1PSDSpartial strand displacement stateTADtopologically associating domainsTEtransposable elementsTFtranscription factorTSCtriple-stranded complexTSStranscription start sitesSEsuper-enhancersSEDsuper-enhancer domainssncRNAsmall non coding RNA