Histone Modifications at Human Enhancers Reflect Global Cell-Type-Specific Gene Expression

Ludwig Institute for Cancer Research, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0653, USA.
Nature (Impact Factor: 41.46). 04/2009; 459(7243):108-12. DOI: 10.1038/nature07829
Source: PubMed


The human body is composed of diverse cell types with distinct functions. Although it is known that lineage specification depends on cell-specific gene expression, which in turn is driven by promoters, enhancers, insulators and other cis-regulatory DNA sequences for each gene, the relative roles of these regulatory elements in this process are not clear. We have previously developed a chromatin-immunoprecipitation-based microarray method (ChIP-chip) to locate promoters, enhancers and insulators in the human genome. Here we use the same approach to identify these elements in multiple cell types and investigate their roles in cell-type-specific gene expression. We observed that the chromatin state at promoters and CTCF-binding at insulators is largely invariant across diverse cell types. In contrast, enhancers are marked with highly cell-type-specific histone modification patterns, strongly correlate to cell-type-specific gene expression programs on a global scale, and are functionally active in a cell-type-specific manner. Our results define over 55,000 potential transcriptional enhancers in the human genome, significantly expanding the current catalogue of human enhancers and highlighting the role of these elements in cell-type-specific gene expression.

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    • "These assays can measure specific changes to chromatin configuration near transcription start sites, providing accurate identification of genes with altered transcriptional regulation in a condition of interest. Incorporating these data into transcription factor binding predictions can improve the identification of genes that are transcriptionally regulated (Heintzman et al., 2009), as well as the transcription factors that are regulating the genes (Cuellar-Partida et al., 2012;Pique-Regi et al., 2011). To date, however, measurement of epigenetic perturbations alongside miRNA perturbation has been studied only in context of general changes () and not used to characterize miRNA regulatory networks. "
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    • "The involvement of specific enhancer elements in these events is of particular interest as they undergo rapid epigenetic setting, for example, by becoming activated or poised with histone H3 lysine 27 acetylation (H3K27ac) and H3K27me3 modifications, respectively (Creyghton et al., 2010; Heintzman et al., 2009; Nord et al., 2013; Rada-Iglesias et al., 2011; Zentner et al., 2011). Similarly , the transition from naı¨ve embryonic stem cells (ESCs) to epiblast-like cells (EpiLCs) and epiblast stem cells (EpiSCs) is accompanied by rapid changes in enhancer usage (Buecker et al., 2014; Factor et al., 2014). "
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    • "However, the mechanisms that restrict enhancer activity to a single promoter in the presence of multiple promoter choices are unclear. Enhancers carry a unique chromatin structure characterized by the presence of 3K4me1 (Heintzman et al. 2009). In addition, histone H3K27ac distinguishes active enhancers from poised enhancers (Creyghton et al. 2010). "
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