Transposable Elements and DNA Methylation Create in Embryonic Stem Cells Human-Specific Regulatory Sequences Associated with Distal Enhancers and Noncoding RNAs.
Bottom Line: Despite significant progress in the structural and functional characterization of the human genome, understanding of the mechanisms underlying the genetic basis of human phenotypic uniqueness remains limited.Preliminary estimates suggest that emergence of one novel NANOG-binding site detectable in hESC required 466 years of evolution.A proximity placement model is proposed explaining how a 33-47% excess of NANOG, CTCF, and POU5F1 proteins immobilized on a DNA scaffold may play a functional role at distal regulatory elements.
Affiliation: Institute of Engineering in Medicine, University of California, San Diego The Stanford University School of Medicine, Department of Surgery, Stanford, California email@example.com firstname.lastname@example.org.Show MeSH
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Mentions: Consistent with the recent reports of the increased LTR7 transcription in hESC (Kelley and Rinn 2012; Santoni et al. 2012; Xie et al. 2013; Lu et al. 2014), transcriptional activity of the LTR7-embedded human-specific NANOG-binding sites was frequently observed in hESC (fig. 1). Subsequent analytical efforts were focused on the 33- and 24-nt LTR7-derived sequences of small noncoding RNAs (LTR7 sncRNAs), which were often represented among LTR7-associated transcripts detected in hESCs (figs. 1 and 3 and supplementary fig. S4, Supplementary Material online). The initial analysis was concentrated on the genome-wide assessment of the fully conserved 33- and 24-nt LTR7 sncRNA-encoding loci, defined as the full-length sequences with 100% identity, no gaps, and no mismatches. Both sequences were classified as primate-specific, because 1) there are no full-length 33- and 24-nt LTR7 sequences in either the mouse or rat genomes, and 2) chromosomal positions for 89% of the genomic loci encoding 33-nt LTR7 sncRNAs are conserved in primate genomes, with most significant similarities noted between the human genome and those of chimpanzee and gorilla (fig. 3 and supplementary fig. S4, Supplementary Material online). Reflecting their common origin, chromosomal distributions of 33- and 24-nt sequences in the human genome manifest highly correlated patterns (r = 0.865; P < 0.0001). However, the number of loci encoding 24-nt LTR7 sncRNAs is 8.6-fold higher than that for 33-nt transcripts in the human genome (1,129 vs. 130 loci, respectively, in the hg19 human genome reference database). Additional analysis of this phenomenon is presented in the supplementary material, Supplementary Material online.Fig. 3.—
Affiliation: Institute of Engineering in Medicine, University of California, San Diego The Stanford University School of Medicine, Department of Surgery, Stanford, California email@example.com firstname.lastname@example.org.