Dataset Information

Enhancers in embryonic stem cells are enriched for transposable elements and genetic variations associated with cancers.

ABSTRACT: Using an enhancer-associated epigenetic signature, we made genome-wide predictions of transcriptional enhancers in human B and T lymphocytes and embryonic stem cells (ES cells). We validated and characterized the predicted enhancers using four types of information, including overlap with other genomic marks for enhancers; association with cell-type-specific genes; enrichment of cell-type-specific transcription factor binding sites; and genetic polymorphisms in predicted enhancers. We find that enhancers from ES cells, but not B or T cells, are significantly enriched for DNA sequences derived from transposable elements. This may be due to the generally relaxed repressive epigenetic state and increased activity of transposable elements in ES cells. We demonstrate that the wealth of new enhancer sequences discerned here provides an invaluable resource for the functional annotation of gene-distal single nucleotide polymorphisms identified through expression quantitative trait loci and genome-wide association studies analyses. Notably, we find GWAS SNPs associated with various cancers are enriched in ES cell enhancers. In comparison, GWAS SNPs associated with diseases due to immune dysregulation are enriched in B and T cell enhancers.

SUBMITTER: Teng L

PROVIDER: S-EPMC3177211 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Enhancers in embryonic stem cells are enriched for transposable elements and genetic variations associated with cancers.

Teng Li L Firpi Hiram A HA Tan Kai K

Nucleic acids research 20110617 17

Using an enhancer-associated epigenetic signature, we made genome-wide predictions of transcriptional enhancers in human B and T lymphocytes and embryonic stem cells (ES cells). We validated and characterized the predicted enhancers using four types of information, including overlap with other genomic marks for enhancers; association with cell-type-specific genes; enrichment of cell-type-specific transcription factor binding sites; and genetic polymorphisms in predicted enhancers. We find that e ...[more]

PMID: 21685454

Similar Datasets

Project description: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.

Dataset Information

Enhancers in embryonic stem cells are enriched for transposable elements and genetic variations associated with cancers.

Publications

Enhancers in embryonic stem cells are enriched for transposable elements and genetic variations associated with cancers.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets