ChromHMM: automating chromatin-state discovery and characterization

Ernst, Jason; Kellis, M

doi:10.1038/nmeth.1906

Cited by 2,293 publications

(2,576 citation statements)

References 6 publications

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“…We performed ChromHMM [26] with five active histone marks (H4K5acK8ac, H3K4me1, H3K27ac, H3K4me3, and H3K36me3), two inactive histone marks (H3K27me3 and H3K9me3), and BRD2. Based on twenty emission states, we successfully recapitulated the known chromatin state patterns (Figure 3(c), Fig.…”

Section: Resultsmentioning

confidence: 99%

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JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

Handoko¹,

Kaczkowski²,

Hon³

et al. 2018

Epigenetics

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The bromodomain and extra-terminal domain (BET) proteins are promising drug targets for cancer and immune diseases. However, BET inhibition effects have been studied more in the context of bromodomain-containing protein 4 (BRD4) than BRD2, and the BET protein association to histone H4-hyperacetylated chromatin is not understood at the genome-wide level. Here, we report transcription start site (TSS)-resolution integrative analyses of ChIP-seq and transcriptome profiles in human non-small cell lung cancer (NSCLC) cell line H23. We show that di-acetylation at K5 and K8 of histone H4 (H4K5acK8ac) co-localizes with H3K27ac and BRD2 in the majority of active enhancers and promoters, where BRD2 has a stronger association with H4K5acK8ac than H3K27ac. Although BET inhibition by JQ1 led to complete reduction of BRD2 binding to chromatin, only local changes of H4K5acK8ac levels were observed, suggesting that recruitment of BRD2 does not influence global histone H4 hyperacetylation levels. This finding supports a model in which recruitment of BET proteins via histone H4 hyperacetylation is predominant over hyperacetylation of histone H4 by BET protein-associated acetyltransferases. In addition, we found that a remarkable number of BRD2-bound genes, including MYC and its downstream target genes, were transcriptionally upregulated upon JQ1 treatment. Using BRD2-enriched sites and transcriptional activity analysis, we identified candidate transcription factors potentially involved in the JQ1 response in BRD2-dependent and -independent manner.

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Section: Resultsmentioning

confidence: 99%

“…We used ChromHMM software [26] to identify chromatin states and to perform genome wide state annotation based on combination of H3K4me1, H3K4me3, H3K27ac, H4KacK8ac, H3K36me3, H3K9me3, H3K27me3, and BRD2. We used BinarizeBam to binarize each the genome into 200 nt bins.…”

Section: Methodsmentioning

confidence: 99%

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

Handoko¹,

Kaczkowski²,

Hon³

et al. 2018

Epigenetics

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“…It was proposed that specific combinations of modifications at given locus form a so called "histone code", which is read by other proteins to bring about distinct downstream events [61]. High-resolution mapping of numerous histone modifications in multiple cell types contributed to detection of most common combinations and associated functional genomic elements [62][63][64] and allowed segmentation of the genome into distinct domains based on the levels of various modifications [62,63,65]. Although specific histone modification combinations generally reflect the identity of the underlying DNA element, recent study has shown that actual levels of modification do not necessarily reflect the predicted regulatory activity [66].…”

Section: Promoters Are Marked By Specific Histone Modificationsmentioning

confidence: 99%

Promoter architectures and developmental gene regulation

Haberle

Lenhard

2016

Seminars in Cell & Developmental Biology

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Core promoters are minimal regions sufficient to direct accurate initiation of transcription and are crucial for regulation of gene expression. They are highly diverse in terms of associated core promoter motifs, underlying sequence composition and patterns of transcription initiation.Distinctive features of promoters are also seen at the chromatin level, including nucleosome positioning patterns and presence of specific histone modifications. Recent advances in identifying and characterizing promoters using next-generation sequencing-based technologies have provided the basis for their classification into functional groups and have shed light on their modes of regulation, with important implications for transcriptional regulation in development.This review discusses the methodology and the results of genome-wide studies that provided insight into the diversity of RNA polymerase II promoter architectures in vertebrates and other Metazoa, and the association of these architectures with distinct modes of regulation in embryonic development and differentiation.

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“…Then, we identified regulatory elements including enhancers and promoters estimated by chromatin states in the haplotype blocks across 98 healthy human tissues/normal cell lines available in the ENCODE Project and the Epigenomics Roadmap Project (Encode and Consortium 2011; Chadwick, 2012). The regulatory elements were annotated by an algorithm named ChromHMM, and data were downloaded from HaploReg3 (Ernst & Kellis, 2012; Ward & Kellis, 2012). To evaluate whether GWAS loci were enriched with regulatory elements and corresponded to the DNase I‐hypersensitive sites (DHSs) in muscle tissues, we performed a promoter/enhancer enrichment analysis using a hypergeometric test to compare the abundance of regulatory elements in muscle tissues (9 relevant muscle tissues/cell lines) to nonmuscle tissues (89 tissues/cell lines) in the haplotype blocks of a GWAS locus.…”

Section: Subjectsmentioning

confidence: 99%

GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium

et al. 2016

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SummaryDecline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta‐analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P‐value< 5 × 10−8) and 39 suggestive (P‐value< 5 × 10−5) associations were observed from meta‐analysis of the discovery cohorts. After meta‐analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P‐value = 5.20 × 10−10). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer‐binding protein‐β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.

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ChromHMM: automating chromatin-state discovery and characterization

Cited by 2,293 publications

References 6 publications

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

Promoter architectures and developmental gene regulation

GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium

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