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Transposable Elements and DNA Methylation Create in Embryonic Stem Cells Human-Specific Regulatory Sequences Associated with Distal Enhancers and Noncoding RNAs.

Glinsky GV - Genome Biol Evol (2015)

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.

View Article: PubMed Central - PubMed

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.

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hESC genomic maps of NANOG-binding sites, adjacent 5hmC, and functional hESC enhancer/gene pairs involved in enhancer-coding gene interactions. Snapshots of base-resolution 5hmC maps in the H1-hESC genome in close proximity to the human-specific NANOG-binding sites located near functional hESC enhancers and involved in high-confidence enhancer-target gene interactions, as reported by Xie et al. (2013). Only predicted enhancer-gene pairs with a P value ≤ 0.0001 were considered in the analysis. Also shown are genomic positions of the human-specific NANOG-binding sites (horizontal red bars), hESC enhancers, transcription start sites (TSS) of enhancer-targeted protein-coding genes, and maps of hESC enhancer-gene interaction pairs in H1-hESC (semitransparent green arcs). Positive blue bar values indicate the 5hmC content on the (+) Watson strand of DNA, whereas negative values indicate the 5hmC content on the (−) Crick strand. For 5hmC values, the vertical axis limits are − 50% to + 50%. Note that human-specific NANOG-binding sites (red horizontal bars marked by the NANOG signs) are placed in the heart of the large-scale hESC regulatory domains near functional distal enhancers within high-complexity multidimensional regulatory networks of interacting enhancer-gene pairs (A) as well as within bidirectional (supplementary fig. S7, Supplementary Material online) distal regulatory domains. Examples of 5hmC patterns identified near human-specific NANOG-binding sites on all human chromosomes are shown in (B) (see also supplementary fig. S7, Supplementary Material online). The exact genomic positions of 5hmC are indicated by blue vertical bars, NANOG-binding sites coordinates are depicted by red horizontal bars (unique to human loci), red arrows (primate-specific sequences), and red stars (sites common with rodents) based on the hg18 release of the human genome reference database. Note that human- and primate-specific NANOG-binding sequences are located near hESC enhancers, whereas NANOG-binding sites common with rodents are placed next to the TSS of protein-coding genes. Examples of common 5hmC three- to eight-letter symbols utilized to create a large variety of 5hmC patterns near human-specific NANOG-binding sites are shown in the yellow box (B, top left panel).
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evv081-F5: hESC genomic maps of NANOG-binding sites, adjacent 5hmC, and functional hESC enhancer/gene pairs involved in enhancer-coding gene interactions. Snapshots of base-resolution 5hmC maps in the H1-hESC genome in close proximity to the human-specific NANOG-binding sites located near functional hESC enhancers and involved in high-confidence enhancer-target gene interactions, as reported by Xie et al. (2013). Only predicted enhancer-gene pairs with a P value ≤ 0.0001 were considered in the analysis. Also shown are genomic positions of the human-specific NANOG-binding sites (horizontal red bars), hESC enhancers, transcription start sites (TSS) of enhancer-targeted protein-coding genes, and maps of hESC enhancer-gene interaction pairs in H1-hESC (semitransparent green arcs). Positive blue bar values indicate the 5hmC content on the (+) Watson strand of DNA, whereas negative values indicate the 5hmC content on the (−) Crick strand. For 5hmC values, the vertical axis limits are − 50% to + 50%. Note that human-specific NANOG-binding sites (red horizontal bars marked by the NANOG signs) are placed in the heart of the large-scale hESC regulatory domains near functional distal enhancers within high-complexity multidimensional regulatory networks of interacting enhancer-gene pairs (A) as well as within bidirectional (supplementary fig. S7, Supplementary Material online) distal regulatory domains. Examples of 5hmC patterns identified near human-specific NANOG-binding sites on all human chromosomes are shown in (B) (see also supplementary fig. S7, Supplementary Material online). The exact genomic positions of 5hmC are indicated by blue vertical bars, NANOG-binding sites coordinates are depicted by red horizontal bars (unique to human loci), red arrows (primate-specific sequences), and red stars (sites common with rodents) based on the hg18 release of the human genome reference database. Note that human- and primate-specific NANOG-binding sequences are located near hESC enhancers, whereas NANOG-binding sites common with rodents are placed next to the TSS of protein-coding genes. Examples of common 5hmC three- to eight-letter symbols utilized to create a large variety of 5hmC patterns near human-specific NANOG-binding sites are shown in the yellow box (B, top left panel).

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.—


Transposable Elements and DNA Methylation Create in Embryonic Stem Cells Human-Specific Regulatory Sequences Associated with Distal Enhancers and Noncoding RNAs.

Glinsky GV - Genome Biol Evol (2015)

hESC genomic maps of NANOG-binding sites, adjacent 5hmC, and functional hESC enhancer/gene pairs involved in enhancer-coding gene interactions. Snapshots of base-resolution 5hmC maps in the H1-hESC genome in close proximity to the human-specific NANOG-binding sites located near functional hESC enhancers and involved in high-confidence enhancer-target gene interactions, as reported by Xie et al. (2013). Only predicted enhancer-gene pairs with a P value ≤ 0.0001 were considered in the analysis. Also shown are genomic positions of the human-specific NANOG-binding sites (horizontal red bars), hESC enhancers, transcription start sites (TSS) of enhancer-targeted protein-coding genes, and maps of hESC enhancer-gene interaction pairs in H1-hESC (semitransparent green arcs). Positive blue bar values indicate the 5hmC content on the (+) Watson strand of DNA, whereas negative values indicate the 5hmC content on the (−) Crick strand. For 5hmC values, the vertical axis limits are − 50% to + 50%. Note that human-specific NANOG-binding sites (red horizontal bars marked by the NANOG signs) are placed in the heart of the large-scale hESC regulatory domains near functional distal enhancers within high-complexity multidimensional regulatory networks of interacting enhancer-gene pairs (A) as well as within bidirectional (supplementary fig. S7, Supplementary Material online) distal regulatory domains. Examples of 5hmC patterns identified near human-specific NANOG-binding sites on all human chromosomes are shown in (B) (see also supplementary fig. S7, Supplementary Material online). The exact genomic positions of 5hmC are indicated by blue vertical bars, NANOG-binding sites coordinates are depicted by red horizontal bars (unique to human loci), red arrows (primate-specific sequences), and red stars (sites common with rodents) based on the hg18 release of the human genome reference database. Note that human- and primate-specific NANOG-binding sequences are located near hESC enhancers, whereas NANOG-binding sites common with rodents are placed next to the TSS of protein-coding genes. Examples of common 5hmC three- to eight-letter symbols utilized to create a large variety of 5hmC patterns near human-specific NANOG-binding sites are shown in the yellow box (B, top left panel).
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evv081-F5: hESC genomic maps of NANOG-binding sites, adjacent 5hmC, and functional hESC enhancer/gene pairs involved in enhancer-coding gene interactions. Snapshots of base-resolution 5hmC maps in the H1-hESC genome in close proximity to the human-specific NANOG-binding sites located near functional hESC enhancers and involved in high-confidence enhancer-target gene interactions, as reported by Xie et al. (2013). Only predicted enhancer-gene pairs with a P value ≤ 0.0001 were considered in the analysis. Also shown are genomic positions of the human-specific NANOG-binding sites (horizontal red bars), hESC enhancers, transcription start sites (TSS) of enhancer-targeted protein-coding genes, and maps of hESC enhancer-gene interaction pairs in H1-hESC (semitransparent green arcs). Positive blue bar values indicate the 5hmC content on the (+) Watson strand of DNA, whereas negative values indicate the 5hmC content on the (−) Crick strand. For 5hmC values, the vertical axis limits are − 50% to + 50%. Note that human-specific NANOG-binding sites (red horizontal bars marked by the NANOG signs) are placed in the heart of the large-scale hESC regulatory domains near functional distal enhancers within high-complexity multidimensional regulatory networks of interacting enhancer-gene pairs (A) as well as within bidirectional (supplementary fig. S7, Supplementary Material online) distal regulatory domains. Examples of 5hmC patterns identified near human-specific NANOG-binding sites on all human chromosomes are shown in (B) (see also supplementary fig. S7, Supplementary Material online). The exact genomic positions of 5hmC are indicated by blue vertical bars, NANOG-binding sites coordinates are depicted by red horizontal bars (unique to human loci), red arrows (primate-specific sequences), and red stars (sites common with rodents) based on the hg18 release of the human genome reference database. Note that human- and primate-specific NANOG-binding sequences are located near hESC enhancers, whereas NANOG-binding sites common with rodents are placed next to the TSS of protein-coding genes. Examples of common 5hmC three- to eight-letter symbols utilized to create a large variety of 5hmC patterns near human-specific NANOG-binding sites are shown in the yellow box (B, top left panel).
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.—

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.

View Article: PubMed Central - PubMed

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.

Show MeSH
Related in: MedlinePlus