Broad H3K4me3 Reveals Increased Transcription Elongation and Enhancer Activity at Tumor Suppressors

Tumor suppressors are mostly defined by inactivating somatic mutations in tumors, yet little is known about their epigenetic features in normal cells. Here, through integrative analysis of 1,134 genome-wide epigenetic profiles and mutations from >8,200 tumor-normal pairs, 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 represents core 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 strongly associated with repression of tumor suppressors. Together, the broad H3K4me3 epigenetic signature we reported here may provide a new direction for the discovery and characterization of novel tumor suppressors. H3K4me3 ChIP-Seq was conducted in 1) liver tumor and matched tissue, 2) lung tumor and matched tissue, 3) cell line A549 grown under normal and flavopiridol treatment conditions.