Identification and characterization of unique to human regulatory sequences in embryonic stem cells reveal associations with transposable elements, distal enhancers, non-coding RNA, and DNA methylation-driven mechanisms of genome editing

Abstract

Despite significant progress in structural and functional characterization of human genome, understanding of mechanisms underlying the genetic basis of human phenotypic uniqueness remains limited. We report that non-randomly distributed transposable element-derived sequences, most notably HERV-H/LTR7 and L1HS, are associated with creation of 99.8% unique to human transcription factor binding sites in genome of embryonic stem cells (ESC). 4,094 unique to human regulatory loci display selective and site-specific binding of critical regulators (NANOG, POU5F1, CTCF, Lamin B1) and are preferentially placed within the matrix of transcriptionally active DNA segments hyper-methylated in ESC. Unique to human NANOG-binding sites are enriched near the rapidly evolving in primates protein-coding genes regulating brain size, pluripotency lncRNAs, hESC enhancers, and 5-hydroxymethylcytosine-harboring regions immediately adjacent to binding sites. We propose a proximity placement model explaining how 33-47% excess of NANOG and POU5F1 proteins immobilized on a DNA scaffold may play a functional role at distal regulatory elements.

47 pages, including 5 figures and 3 tables

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