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Histone modifications at human enhancers reflect global cell-type-specific gene expression
Nathaniel D. Heintzman1,2,12, Gary C. Hon1,3,12, R. David Hawkins1,12, Pouya Kheradpour5, Alexander Stark5,6, Lindsey F. Harp1, Zhen Ye1, Leonard K. Lee1, Rhona K. Stuart1, Christina W. Ching1, Keith A. Ching1, Jessica E. Antosiewicz-Bourget7, Hui Liu8, Xinmin Zhang8, Roland D. Green8, Victor V. Lobanenkov9, Ron Stewart7, James A. Thomson7,10, Gregory E. Crawford11, Manolis Kellis5,6 & Bing Ren1,4
1 Ludwig Institute for Cancer Research,
2 Biomedical Sciences Graduate Program,
3 Bioinformatics Program, and,
4 Department of Cellular and Molecular Medicine, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0653, USA
5 MIT Computer Science and Artificial Intelligence Laboratory, 32 Vassar Street, Cambridge, Massachusetts 02139, USA
6 Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
7 Morgridge Institute for Research, Madison, Wisconsin 53707-7365, USA
8 Roche NimbleGen, Inc., 500 South Rosa Road, Madison, Wisconsin 53719, USA
9 National Institutes of Allergy and Infectious Disease, 5640 Fishers Lane, Rockville, Maryland 20852, USA
10 University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA
11 Institute for Genome Sciences and Policy, and Department of Pediatrics, Duke University, 101 Science Drive, Durham, North Carolina 27708, USA
12 These authors contributed equally to this work.
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.
