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Creation of distal enhancers defines human-specific features of interphase chromatin architecture in embryonic stem cells

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

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

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 May 25, 2017.
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Creation of distal enhancers defines human-specific features of interphase chromatin architecture in embryonic stem cells
Gennadi V. Glinsky
bioRxiv 022913; doi: https://doi.org/10.1101/022913
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Creation of distal enhancers defines human-specific features of interphase chromatin architecture in embryonic stem cells
Gennadi V. Glinsky
bioRxiv 022913; doi: https://doi.org/10.1101/022913

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