Chromatin Stretch Enhancer States Drive Cell-specific Gene Regulation And Harbor Human Disease Risk Variants
PNAS. 2013-10-29;110(44):17921-17926.
- Abstract
- Chromatin-based functional genomic analyses and genomewide association studies (GWASs) together implicate enhancers as critical elements influencing gene expression and risk for common diseases. Here, we performed systematic chromatin and transcriptome profiling in human pancreatic islets. Integrated analysis of islet data with those from nine cell types identified specific and significant enrichment of type 2 diabetes and related quantitative trait GWAS variants in islet enhancers. Our integrated chromatin maps reveal that most enhancers are short (median = 0.8 kb). Each cell type also contains a substantial number of more extended (≥3 kb) enhancers. Interestingly, these stretch enhancers are often tissue-specific and overlap locus control regions, suggesting that they are important chromatin regulatory beacons. Indeed, we show that (i) tissue specificity of enhancers and nearby gene expression increase with enhancer length; (ii) neighborhoods containing stretch enhancers are enriched for important cell type–specific genes; and (iii) GWAS variants associated with traits relevant to a particular cell type are more enriched in stretch enhancers compared with short enhancers. Reporter constructs containing stretch enhancer sequences exhibited tissue-specific activity in cell culture experiments and in transgenic mice. These results suggest that stretch enhancers are critical chromatin elements for coordinating cell type–specific regulatory programs and that sequence variation in stretch enhancers affects risk of major common human diseases. High-throughput sequencing has been coupled to ChIP (ChIP-seq) and mRNA samples (RNA-seq) to survey the genomewide chromatin and transcription profiles in different cell types. Regulatory elements such as promoters, enhancers, insulators, transcribed, and repressed regions are marked by distinct patterns of histone modifications (1), including histone H3 lysine 27 acetylation (H3K27ac), H3K27 trimethylation (H3K27me3), H3K36me3, H3K4 monomethylation (H3K4me1), H3K4me3, and the CCCTC-binding factor (CTCF). Systematic chromatin state identification has recently emerged as a powerful technique to interpret and compare regulatory landscapes within and between cell types (2⇓⇓⇓⇓–7). Such methods use an unsupervised approach to identify recurrent combinations of histone modifications across the genome, thereby producing a map of representative chromatin states that are likely to be biologically relevant.
- Consortium data used in this publication
- GSE51311
- Datasets
- TSTSR536023, TSTSR902979, TSTSR438555, TSTSR333787, TSTSR199780, TSTSR272540, TSTSR101497
- References