Histone modifications at human enhancers reflect global cell-type-specific gene expression

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Abstract
The relative role of promoters, enhancers and other regulatory DNA elements in determining cell-type-specific gene expression is poorly understood. Now a chromatin-immunoprecipitation-based microarray (ChIP-chip) method has been used to generate maps of histone modifications at promoters and enhancers in several different human cell lines. The modification patterns at promoters are found to be largely invariant between cell types, whereas the patterns at most enhancers are specific to a single cell type and correlate with cell-type-specific gene expression. By generating maps of histone modifications at promoters and enhancers in several different human cell lines, it has been possible to determine that although modification patterns at promoters are largely invariant between cell types, the patterns at most enhancers are specific to a single cell type and correlate well with cell-type-specific gene expression. 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 gene1,2,3, 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 genome4,5,6. 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.