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 firstname.lastname@example.org email@example.com.Show MeSH
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Mentions: Functional distal regulatory elements in hESCs are markedly enriched for 5-hydroxymethylcytosine (5hmC), which is most enriched in regions immediately adjacent to sequence motifs of TF-binding sites (Yu et al. 2012). Using a base-resolution map of 5hmC in the hESC genome, I determined that 5hmC is located near 46% and 21% of human-specific NANOG-binding sites within 1-kb and 100-bp windows near human-specific NANOG-binding sites, respectively (fig. 5 and supplementary fig. S7, Supplementary Material online). In contrast, no enrichment of 5hmC nucleotides near human-specific CTCF-binding sites within 1-kb windows was observed. Only 15% of CTCF-binding sites were located near 5hmC, which is significantly lower than the number of human-specific NANOG-binding sites (P < 0.0001). Similarly, no significant enrichment of 5hmC nucleotides was observed near human-specific POU5F1-binding sites. Only 14.9% of POU5F1-binding sites were located within 1 kb of 5hmC, which is significantly lower than the number of colocalization events documented for human-specific NANOG-binding sites (P < 0.0001). These data indicate that a large number of human-specific NANOG-binding sites harbor 5hmC within the canonical CpG context immediately adjacent to TF-binding sequence motifs, because in hESCs nearly all (99.89%) 5hmCs exist in the canonical CpG context (Yu et al. 2012). Additional details of this analysis are reported in the supplementary material, Supplementary Material online.Fig. 5.—
Affiliation: Institute of Engineering in Medicine, University of California, San Diego The Stanford University School of Medicine, Department of Surgery, Stanford, California firstname.lastname@example.org email@example.com.