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

By Nathaniel D. Heintzman, Gary Chung Hon, R. D. Hawkins, Pouya Kheradpour, Alexander Stark, L. F. Harp, Z. Ye, Leonard K. Lee, R. Stuart, Christina W. Ching and 11 more. Nature, 2009

2,528 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/ef82021f1f6f755ff906100fce165a0d276e2e18

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Citations in the corpus

Cancer epigenetics: from mechanism to therapy. (2012, background): “, 2007), whereas H3K4me1 is a modification associated with active enhancers (Heintzman et al., 2009).”
Widespread transcription at neuronal activity-regulated enhancers (2010, neutral): “The assumption in this analysis is that an enhancer is most likely to promote mRNA synthesis of the nearest gene3,25.”
Epigenetics and gene expression (2010, background): “The consistency of these findings in species as diverse as yeast, human and mouse has allowed the use of histone modification ‘signatures’ to search for novel transcribed genes (Ozsolak et al., 2008; Won et al., 2008; Guttman et al., 2009; Heintzman et al., 2007, 2009).”
Cistrome Data Browser: a data portal for ChIP-Seq and chromatin accessibility data in human and mouse (2016, background): “Chromatin profiles in diverse cell types and under various experimental conditions can be used in tissue specific or cell developmental studies (28).”
Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription (2013, background): “Because the complement of active cis-regulatory elements changes across cell types, these findings introduced the notion that enhancers are largely responsible for cell-type-specific gene expression (Heintzman et al., 2009; Thurman et al., 2012; Visel et al., 2009).”
Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. (2010, methodology): “…found to be constitutively associated with both p300 and the H3K4me1hi/H3K4me3lo signature in the cell types and experimental conditions analyzed (Heintzman et al., 2009), we investigated by chromatin immunoprecipitation (ChIP) whether lipopolysaccharide (LPS) stimulation affects p300 binding…”
Functional and mechanistic diversity of distal transcription enhancers (2011, neutral): “Based on such observations, it has been suggested that the human genome might harbor as many as 1 3 10 enhancers (Heintzman et al., 2009).”
Comprehensive analysis of the chromatin landscape in Drosophila (2010, background): “State 3 lacks H3K4me3 and is enriched for H3K4me1, H3K27ac and H3K18ac, similar to mammalian enhancer elements 37 .”
An encyclopedia of mouse DNA elements (Mouse ENCODE) (2012, methodology): “…approaches, including DNaseI hypersensitive sites by DNaseseq [19], DNaseI footprints by digital genomic footprinting [20], RNAseq [21], histone modifications by ChIPseq [22], transcrip tion factor and polymerase occupancy sites by ChIPseq [23], and DNA replication timing by Replichip [24].”
JASPAR 2010: the greatly expanded open-access database of transcription factor binding profiles (2009, background): “The increasing amount of assembled genome sequences, transcriptome data (1), as well as high-throughput studies revealing genome-wide locations of core promoters (2) and enhancer elements (3,4) have resulted in the greatest demand for TF binding site content analyses.”
Transcriptional enhancers: from properties to genome-wide predictions (2014, background): “For example, promoter regions around TSSs are often accessible invariantly across different cell types 70,71 .”
Long non-coding RNAs with enhancer-like function in human (2010, background): “…studies have shown that distal activating sequences/ enhancers can stimulate transcription when placed adjacent to a heterologous promoter, a methodology widely used to validate potential enhancers (Banerji et al., 1983, 1981; Gillies et al., 1983; Heintzman et al., 2009; Kong et al., 1997).”
Architectural protein subclasses shape 3D organization of genomes during lineage commitment. (2013, neutral): “A strong correlation was observed between ES-specific enhancers displaying H3K4me3 Cell 153, 1–15, June 6, 2013 ª2013 Elsevier Inc. 9 (legend on next page) 10 Cell 153, 1–15, June 6, 2013 ª2013 Elsevier Inc. signal and RNA Pol II occupancy, suggesting that enhancers marked by H3K4me3 might have acti”