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: Next, a systematic survey of the genomic regulatory landscape around candidate human-specific NANOG- and CTCF-binding sites was conducted to identify regulatory elements associated with putative human-specific TF-binding events. The following genomic features of regions adjacent to human-specific TF-binding events were observed: 1) Frequent location within lamina-associated domains (LADs) (fig. 1 and supplementary fig. S2, Supplementary Material online), 2) consistent transcriptional activity (fig. 1), and 3) apparent association with domains of differential DNA methylation in hESCs (fig. 2). An example of the enrichment of TF-binding sites within LADs is illustrated in figure 1 for NANOG-binding sites embedded within full-length 6-kb LINE transposons. LADs occupy 42.9% of the human genome (Guelen et al. 2008). Therefore, based on the random distribution model, the expected number of L1-embedded NANOG-binding sites located within LADs is estimated at 72, which is significantly less than the observed number of 104 binding events located within LADs (fig. 1). A significant difference in representations between the NANOG-binding sites embedded within truncated or full-length L1 sequences and those located either within or outside the LAD boundaries was observed. Only 5% of all L1HS- and L1PA2-embedded NANOG-binding sites located within LADs are represented by truncated L1 sequences (fig. 1). In contrast, 15% of L1 retrotransposon-associated NANOG-binding events are located within truncated L1 sequences outside of the LAD boundaries (fig. 1). These data indicate that LADs represent genomic regions that favor the placement and/or retention of full-length L1 sequences harboring human-specific NANOG-binding sites. This phenomenon appears to be L1 retrotransposon-specific, because LTR7-embedded NANOG-binding events are distributed equally within and outside LADs, whereas LTR5_HS-associated NANOG-binding sites are preferentially located outside the LAD boundaries (fig. 1). Similarly, the number of human-specific RNAPII-binding sites located outside LADs is markedly enriched in both K562 and MCF cells and is depleted within LADs in both cell types (fig. 1), which is consistent with previous reports identifying LADs as chromosomal domains with a predominantly repressive chromatin environment and low transcriptional activity (Guelen et al. 2008; Peric-Hupkes et al. 2010).Fig. 2.—
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.