title: Transposable Elements and DNA Methylation Create in Embryonic Stem Cells Human-Specific Regulatory Sequences Associated with Distal Enhancers and Noncoding RNAs.
abstract: 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. Here, I report that transposable element-derived sequences, most notably LTR7/HERV-H, LTR5_Hs, and L1HS, harbor 99.8% of the candidate human-specific regulatory loci (HSRL) with putative transcription factor-binding sites in the genome of human embryonic stem cells (hESC). A total of 4,094 candidate HSRL display selective and site-specific binding of critical regulators (NANOG [Nanog homeobox], POU5F1 [POU class 5 homeobox 1], CCCTC-binding factor [CTCF], Lamin B1), and are preferentially located within the matrix of transcriptionally active DNA segments that are hypermethylated in hESC. hESC-specific NANOG-binding sites are enriched near the protein-coding genes regulating brain size, pluripotency long noncoding RNAs, hESC enhancers, and 5-hydroxymethylcytosine-harboring regions immediately adjacent to binding sites. Sequences of only 4.3% of hESC-specific NANOG-binding sites are present in Neanderthals' genome, suggesting that a majority of these regulatory elements emerged in Modern Humans. Comparisons of estimated creation rates of novel TF-binding sites revealed that there was 49.7-fold acceleration of creation rates of NANOG-binding sites in genomes of Chimpanzees compared with the mouse genomes and further 5.7-fold acceleration in genomes of Modern Humans compared with the Chimpanzees genomes. Preliminary estimates suggest that emergence of one novel NANOG-binding site detectable in hESC required 466 years of evolution. Pathway analysis of coding genes that have hESC-specific NANOG-binding sites within gene bodies or near gene boundaries revealed their association with physiological development and functions of nervous and cardiovascular systems, embryonic development, behavior, as well as development of a diverse spectrum of pathological conditions such as cancer, diseases of cardiovascular and reproductive systems, metabolic diseases, multiple neurological and psychological disorders. 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.
authors.affiliation: Institute of Engineering in Medicine, University of California, San Diego The Stanford University School of Medicine, Department of Surgery, Stanford, California gglinskii@ucsd.edu gglinsky@stanfrod.edu.
authors.forename: Gennadi V
authors.initials: GV
authors.lastname: Glinsky
mesh_terms: D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D002454:Cell Differentiation; D002843:Chromatin / Q000378:metabolism; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D019143:Evolution, Molecular; D015894:Genome, Human; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D009154:Mutation; D000071317:Nanog Homeobox Protein; D034881:Nuclear Lamina / Q000235:genetics; D011323:Primates; D062085:RNA, Long Noncoding / Q000235:genetics; D022661:RNA, Untranslated / Q000235:genetics*; D050436:Regulatory Elements, Transcriptional; D018626:Retroelements; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D018626:Retroelements; D014157:Transcription Factors
keywords: CTCF; L1 retrotransposition; LINE; LTR; LTR7 RNAs; LTR7/HERVH; NANOG; POU5F1 (OCT4); evolution of Modern Humans; human ESC; methyl-cytosine deamination; pluripotent state regulators; primate evolution; repetitive elements; retrotransposons