Broad H3K4me3 is associated with increased transcription elongation and enhancer activity at tumor-suppressor genes

Abstract

Tumor suppressors are mostly defined by inactivating mutations in tumors, yet little is known about their epigenetic features in normal cells. Through integrative analysis of 1,134 genome-wide epigenetic profiles, mutations from >8,200 tumor-normal pairs, and our experimental data from clinical samples, we discovered broad H3K4me3 (wider than 4 kb) as the first epigenetic signature for tumor suppressors in normal cells. Broad H3K4me3 is associated with increased transcription elongation and enhancer activity together leading to exceptionally high gene expression, and is distinct from other broad epigenetic features, such as super-enhancers. Broad H3K4me3 conserved across normal cells may represent pan-cancer tumor suppressors, such as P53 and PTEN, whereas cell-type-specific broad H3K4me3 may indicate cell-identity genes and cell-type-specific tumor suppressors. Furthermore, widespread shortening of broad H3K4me3 in cancers is associated with repression of tumor suppressors. Together, the broad H3K4me3 epigenetic signature provides mutation-independent information for the discovery and characterization of novel tumor suppressors.

OX40 Costimulation Inhibits Foxp3 Expression and Treg Induction via BATF3-Dependent and Independent Mechanisms

“…ATAC-seq was performed at Active Motif (Carlsbad, CA). ATAC-seq peaks were detected with DANPOS2 deregion function (Chen et al, 2015) and visualized using University of California, Santa Cruz (UCSC) genome browser with peak height normalized against the Gapdh locus. Gain and loss regions are defined by height q value < 0.01 and log2 fold change > 2.…”

Understanding super-enhancers

“…But further analysis shows that H3K4me3 broad peaks have better discriminative power for cell lineages than super-enhancers. Moreover, H3K4me3 broad peaks are also found to specifically associate with tumor-suppressor genes, which are conserved in many cell types (Chen et al, 2015). This indicates that different broad epigenetic marks play different roles in regulating gene expression.…”

“…Several other large epigenetic marks are also found to be related with cell identity or tissue specific functions, such as H3K4me3 broad peaks (Benayoun et al, 2014;Chen et al, 2015) and DNA methylation valleys (large hypo-methylate regions) (Jeong et al, 2014;Xie et al, 2013). Evidence shows that those different broad epigenetic marks marked different sets of genes from those marked by super-enhancers, even though they overlap in some genomic regions.…”

ChIP-seq in Studying Epigenetic Mechanisms of Disease and Promoting Precision Medicine: Progresses and Future Directions

“…These broad peaks are preferentially associated with highly expressed tumor suppressors in normal cells [61]. They become much shorter in cancers, leading to repression of the associated tumor suppressors [61]. In systemic lupus erythematosus, an autoimmune disease, broad peaks were often linked to immune response genes [9].…”

“…These broad peaks are preferentially associated with highly expressed tumor suppressors in normal cells [61]. They become much shorter in cancers, leading to repression of the associated tumor suppressors [61].…”