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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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Characterization of genomic features associated with human ESC-specific NANOG- and CTCF-binding sites. Location of full-length L1 TE sequences containing human ESC-specific NANOG-binding sites is enriched within LADs (A). In the hESC genome, there are 184 human-specific NANOG-binding sites that are embedded within 167 full-length and 17 truncated L1HS and L1PA2 sequences, 110 of which are located within LADs (A, top panel). In total, 104 of 110 (95%) of the L1HS and L1PA2 sequences containing human-specific NANOG-binding sites and located within LADs are preserved as full-length (5,962–6,189 bp) L1 retrotransposons (A, top panel), indicating that the conservation of the full-length L1 TE containing human-specific NANOG-binding sites is significantly higher within LADs. In contrast, the majority of LTR5_HS-embedded human-specific NANOG-binding sites is found outside of LADs, whereas LTR7-embedded human-specific NANOG-binding sites are equally distributed within and outside of LADs (A, bottom panel). Distinct placement patterns within LADs of 446 human-specific TF-binding sites for five different regulatory proteins (B). Note that a significantly higher fraction than expected by chance of RNAPII-binding sites is located outside of LADs (B) in contrast to other TF-binding sites. LTR7-derived sncRNAs represent the predominant type of sncRNAs generated by transcriptional activity of the human-specific NANOG-binding sites in hESCs and are transcribed from the loci equally distributed within and outside the LADs (C, D).
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evv081-F1: Characterization of genomic features associated with human ESC-specific NANOG- and CTCF-binding sites. Location of full-length L1 TE sequences containing human ESC-specific NANOG-binding sites is enriched within LADs (A). In the hESC genome, there are 184 human-specific NANOG-binding sites that are embedded within 167 full-length and 17 truncated L1HS and L1PA2 sequences, 110 of which are located within LADs (A, top panel). In total, 104 of 110 (95%) of the L1HS and L1PA2 sequences containing human-specific NANOG-binding sites and located within LADs are preserved as full-length (5,962–6,189 bp) L1 retrotransposons (A, top panel), indicating that the conservation of the full-length L1 TE containing human-specific NANOG-binding sites is significantly higher within LADs. In contrast, the majority of LTR5_HS-embedded human-specific NANOG-binding sites is found outside of LADs, whereas LTR7-embedded human-specific NANOG-binding sites are equally distributed within and outside of LADs (A, bottom panel). Distinct placement patterns within LADs of 446 human-specific TF-binding sites for five different regulatory proteins (B). Note that a significantly higher fraction than expected by chance of RNAPII-binding sites is located outside of LADs (B) in contrast to other TF-binding sites. LTR7-derived sncRNAs represent the predominant type of sncRNAs generated by transcriptional activity of the human-specific NANOG-binding sites in hESCs and are transcribed from the loci equally distributed within and outside the LADs (C, D).

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.—


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)

Characterization of genomic features associated with human ESC-specific NANOG- and CTCF-binding sites. Location of full-length L1 TE sequences containing human ESC-specific NANOG-binding sites is enriched within LADs (A). In the hESC genome, there are 184 human-specific NANOG-binding sites that are embedded within 167 full-length and 17 truncated L1HS and L1PA2 sequences, 110 of which are located within LADs (A, top panel). In total, 104 of 110 (95%) of the L1HS and L1PA2 sequences containing human-specific NANOG-binding sites and located within LADs are preserved as full-length (5,962–6,189 bp) L1 retrotransposons (A, top panel), indicating that the conservation of the full-length L1 TE containing human-specific NANOG-binding sites is significantly higher within LADs. In contrast, the majority of LTR5_HS-embedded human-specific NANOG-binding sites is found outside of LADs, whereas LTR7-embedded human-specific NANOG-binding sites are equally distributed within and outside of LADs (A, bottom panel). Distinct placement patterns within LADs of 446 human-specific TF-binding sites for five different regulatory proteins (B). Note that a significantly higher fraction than expected by chance of RNAPII-binding sites is located outside of LADs (B) in contrast to other TF-binding sites. LTR7-derived sncRNAs represent the predominant type of sncRNAs generated by transcriptional activity of the human-specific NANOG-binding sites in hESCs and are transcribed from the loci equally distributed within and outside the LADs (C, D).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4494056&req=5

evv081-F1: Characterization of genomic features associated with human ESC-specific NANOG- and CTCF-binding sites. Location of full-length L1 TE sequences containing human ESC-specific NANOG-binding sites is enriched within LADs (A). In the hESC genome, there are 184 human-specific NANOG-binding sites that are embedded within 167 full-length and 17 truncated L1HS and L1PA2 sequences, 110 of which are located within LADs (A, top panel). In total, 104 of 110 (95%) of the L1HS and L1PA2 sequences containing human-specific NANOG-binding sites and located within LADs are preserved as full-length (5,962–6,189 bp) L1 retrotransposons (A, top panel), indicating that the conservation of the full-length L1 TE containing human-specific NANOG-binding sites is significantly higher within LADs. In contrast, the majority of LTR5_HS-embedded human-specific NANOG-binding sites is found outside of LADs, whereas LTR7-embedded human-specific NANOG-binding sites are equally distributed within and outside of LADs (A, bottom panel). Distinct placement patterns within LADs of 446 human-specific TF-binding sites for five different regulatory proteins (B). Note that a significantly higher fraction than expected by chance of RNAPII-binding sites is located outside of LADs (B) in contrast to other TF-binding sites. LTR7-derived sncRNAs represent the predominant type of sncRNAs generated by transcriptional activity of the human-specific NANOG-binding sites in hESCs and are transcribed from the loci equally distributed within and outside the LADs (C, D).
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.—

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