Dataset Information

Identification of H3K4me1-associated proteins at mammalian enhancers.

ABSTRACT: Enhancers act to regulate cell-type-specific gene expression by facilitating the transcription of target genes. In mammalian cells, active or primed enhancers are commonly marked by monomethylation of histone H3 at lysine 4 (H3K4me1) in a cell-type-specific manner. Whether and how this histone modification regulates enhancer-dependent transcription programs in mammals is unclear. In this study, we conducted SILAC mass spectrometry experiments with mononucleosomes and identified multiple H3K4me1-associated proteins, including many involved in chromatin remodeling. We demonstrate that H3K4me1 augments association of the chromatin-remodeling complex BAF to enhancers in vivo and that, in vitro, H3K4me1-marked nucleosomes are more efficiently remodeled by the BAF complex. Crystal structures of the BAF component BAF45C indicate that monomethylation, but not trimethylation, is accommodated by BAF45C's H3K4-binding site. Our results suggest that H3K4me1 has an active role at enhancers by facilitating binding of the BAF complex and possibly other chromatin regulators.

SUBMITTER: Local A

PROVIDER: S-EPMC6007000 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Identification of H3K4me1-associated proteins at mammalian enhancers.

Local Andrea A Huang Hui H Albuquerque Claudio P CP Singh Namit N Lee Ah Young AY Wang Wei W Wang Chaochen C Hsia Judy E JE Shiau Andrew K AK Ge Kai K Corbett Kevin D KD Wang Dong D Zhou Huilin H Ren Bing B

Nature genetics 20171218 1

Enhancers act to regulate cell-type-specific gene expression by facilitating the transcription of target genes. In mammalian cells, active or primed enhancers are commonly marked by monomethylation of histone H3 at lysine 4 (H3K4me1) in a cell-type-specific manner. Whether and how this histone modification regulates enhancer-dependent transcription programs in mammals is unclear. In this study, we conducted SILAC mass spectrometry experiments with mononucleosomes and identified multiple H3K4me1- ...[more]

PMID: 29255264

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Project description:BackgroundDNA methylation at promoters is largely correlated with inhibition of gene expression. However, the role of DNA methylation at enhancers is not fully understood, although a crosstalk with chromatin marks is expected. Actually, there exist contradictory reports about positive and negative correlations between DNA methylation and H3K4me1, a chromatin hallmark of enhancers.ResultsWe investigated the relationship between DNA methylation and active chromatin marks through genome-wide correlations, and found anti-correlation between H3K4me1 and H3K4me3 enrichment at low and intermediate DNA methylation loci. We hypothesized "seesaw" dynamics between H3K4me1 and H3K4me3 in the low and intermediate DNA methylation range, in which DNA methylation discriminates between enhancers and promoters, marked by H3K4me1 and H3K4me3, respectively. Low methylated regions are H3K4me3 enriched, while those with intermediate DNA methylation levels are progressively H3K4me1 enriched. Additionally, the enrichment of H3K27ac, distinguishing active from primed enhancers, follows a plateau in the lower range of the intermediate DNA methylation level, corresponding to active enhancers, and decreases linearly in the higher range of the intermediate DNA methylation. Thus, the decrease of the DNA methylation switches smoothly the state of the enhancers from a primed to an active state. We summarize these observations into a rule of thumb of one-out-of-three methylation marks: "In each genomic region only one out of these three methylation marks {DNA methylation, H3K4me1, H3K4me3} is high. If it is the DNA methylation, the region is inactive. If it is H3K4me1, the region is an enhancer, and if it is H3K4me3, the region is a promoter". To test our model, we used available genome-wide datasets of H3K4 methyltransferases knockouts. Our analysis suggests that CXXC proteins, as readers of non-methylated CpGs would regulate the "seesaw" mechanism that focuses H3K4me3 to unmethylated sites, while being repulsed from H3K4me1 decorated enhancers and CpG island shores.ConclusionsOur results show that DNA methylation discriminates promoters from enhancers through H3K4me1-H3K4me3 seesaw mechanism, and suggest its possible function in the inheritance of chromatin marks after cell division. Our analyses suggest aberrant formation of promoter-like regions and ectopic transcription of hypomethylated regions of DNA. Such mechanism process can have important implications in biological process in where it has been reported abnormal DNA methylation status such as cancer and aging.

Dataset Information

Identification of H3K4me1-associated proteins at mammalian enhancers.

Publications

Identification of H3K4me1-associated proteins at mammalian enhancers.

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