Transposable elements have rewired the core regulatory network of human embryonic stem cells

Abstract

Detection of new genomic control elements is critical in understanding transcriptional regulatory networks in their entirety. We studied the genome-wide binding locations of three key regulatory proteins (POU5F1, also known as OCT4; NANOG; and CTCF) in human and mouse embryonic stem cells. In contrast to CTCF, we found that the binding profiles of OCT4 and NANOG are markedly different, with only approximately 5% of the regions being homologously occupied. We show that transposable elements contributed up to 25% of the bound sites in humans and mice and have wired new genes into the core regulatory network of embryonic stem cells. These data indicate that species-specific transposable elements have substantially altered the transcriptional circuitry of pluripotent stem cells.

The Short Isoform of NF‐YA Belongs to the Embryonic Stem Cell Transcription Factor Circuitry

“…On the right part, comparison of predicted in silico data with in vivo ChIP-Seq data of NF-YA derived from Tiwari et al [21], and the calculated p-values. (B): TFBS analysis of mouse [6] and human [28] NANOG loci in promoters with Pscan, using JASPAR and TRANSFAC matrices. (C): De novo motif discovery analysis using Weeder, on 100 bp large NANOG peaks located in promoters of human and mESCs.…”

“…5B, left panel). We then turned to the larger collection of NANOG sites described in human ESCs [28]: as shown in Figure 5B (right panel), the NF-Y matrix is also enriched, with E2F1, MIZF, ELK4, and GABPA: while not at the top of the list, it does have a very significant p-value. To further substantiate and define these data, we performed de novo motif discovery with the Weeder software [30], interrogating sequences within 100 bp of the NANOG ChIP-Seq promoter peaks: the results in Figure 5C indicate that the CCAAT sequence, in either orientation, comes as third in the ranking of the mESCs dataset (upper panel) and first in the larger dataset of hESC NANOG peaks (lower panel).…”

“…We analyzed the sites of several TFs-E2F1, NANOG, KLF4, SOX2, ESRRB, STAT3, OCT4, and CTCF-for which ChIP-Seq data in mESCs are available [6,27,28], including NF-Y [23]. We retrieved the promoters of genes bound by these TFs and scanned them with Pscan; using the latest NF-Y positional sequence frequency matrix, we have gathered from genomic studies [11], at a score of 0.8, which recovers most bona fide NF-Y sites.…”

Genomic regions harboring insecticide resistance-associated Cyp genes are enriched by transposable element fragments carrying putative transcription factor binding sites in two sibling Drosophila species

“…These sequences can affect the expression of adjacent genes by introducing regulatory binding sites (Conte et al, 2002;Jordan et al, 2003;Kunarso et al, 2010;Molineris et al, 2011;Rebollo et al, 2012;Schmid and Bucher, 2010;Thornburg et al, 2006;Wang et al, 2007Wang et al, , 2009) into geneflanking regions. Daborn et al (2002) reported that the insecticide resistance mapping to the DDT-R locus of D. melanogaster is due to the over-expression of one gene, Cyp6g1, and that a single Cyp6g1 allele linked to this resistance is distributed worldwide.…”

Principles for the post-GWAS functional characterisation of risk loci

“…Unlike core promoters (at transcription start sites of genes), distal regulatory sequences such as enhancers are often cell-type specific 11 and thus may explain the tissue and disease specific nature of common susceptibility alleles. Studying histone modifications or DNase sensitivity (or hypersensitivity) has proven to be a powerful approach to annotating tissue specific regulatory elements 12,13 , and is more informative than studying conservation, since regulatory elements may be unconstrained across mammalian evolution [14][15][16] . Using chromatin annotations to identify putative functional SNPs within regulatory sequences at known susceptibility loci has been proposed recently 17 .…”