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: To determine whether repetitive elements contributed to the creation of putative human-specific TF-binding sites, the sequences of 200-bp windows centered at the middle of the TF-binding sites were intersected with the RepeatMasker database track of the University of California Santa Cruz (UCSC) Genome Browser (http://www.repeatmasker.org/, last accessed May 20, 2015). Each overlapping event was tabulated and the numbers of overlaps of each TF’s binding event with specific repetitive elements were calculated. Notably, 99.8% (3,797 of 3,803) of human-specific TF-binding sites were found embedded within repetitive elements, which is significantly higher than the proportion expected by chance (P << 0.0001; hypergeometric distribution test). Follow-up analyses indicated that the “99% rule” is not limited to the NANOG-, OCT4-, and CTCF-binding sites and seems to have broad relevance. All human-specific binding events identified for five different regulatory proteins (SOX2, RNAPII [RNA polymerase II], TAF1, KLF4, and p300) mapped within repeat-derived sequences in the reference human genome database (table 1 and fig. 1).Fig. 1.—
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.