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.

Prenatal Air Pollution Exposures, DNA Methyl Transferase Genotypes, and Associations with Newborn LINE1 and Alu Methylation and Childhood Blood Pressure and Carotid Intima-Media Thickness in the Children’s Health Study

“…During embryogenesis, transcriptional activities of the common elements LINE1 (long interspersed nuclear elements) and Alu increase markedly for a short period of time following genome-wide demethylation at the 2-cell stage but decrease back to the basal level before genome-wide remethylation and are thought to be maintained at a relatively constant hypermethylated state thereafter in somatic cells (Guo et al 2014; Smith et al 2014). This brief activity early in embryogenesis may lead to the creation of human-specific transcription factor binding sites associated with a pluripotent stem cell phenotype (Glinsky 2015). Therefore, altered DNA methylation during this critical embryonic stage may have broad potential to affect downstream regulatory function in the fetus.…”

The involvement of human endogenous retroviruses K (HERV-K) in aging processes via induction of inflammation

“…Intriguingly, it is reported that partial reprogramming by expression of Oct4, Sox2, Klf4, and c-Myc (OSKM) improve cellular and physiological hallmarks of aging and extends the lifespan of mice with premature aging (Ocampo et al, 2016). It is probable that interactions between pluripotency factors and retrotransposons (Glinsky, 2015) coordinate and execute the epigenetic program that controls individual development.…”

“…For example, syncytin is a product of the activity of human endogenous viruses W (HERV-W) aids in normal placental development during pregnancy (Mi et al, 2000). Almost all regulatory loci with pluripotency transcription factor-binding sites are located in LTR7/HERV-H, LTR5/HERV-K, and L1HS (human specific) that are distinct from other genomes (Glinsky, 2015). Moreover, ERVs are controlled in embryonic development by the action of TRIM28/KAP1 (Rowe et al, 2010).…”

On the Concept Of Retrotransposons: Controlling Genome and Making Stress Memories

“…Noteworthy, they documented that 18% and 31% of total transcription start sites in mouse and human, respectively, are located within retrotransposon sequences [2ofgenetic8] . Beyond protein-coding genes, retrotransposons provide promoters and enhancers for long noncoding RNAs (lncRNAs) [84,[87][88][89] . In addition, a large number of gene enhancers are ʺdonatedʺ by retrotransposons, providing the ability of tissue-and species-specific gene expression [84,90,91] .…”