Broad H3K4me3 peaks are specifically associated with increased expression of tumor suppressors.
Major finding: Broad H3K4me3 peaks are specifically associated with increased expression of tumor suppressors.
Mechanism: Broad H3K4me3 promotes transcription elongation and enhancer activity at tumor-suppressor genes.
Impact: Broad H3K4me3 may be useful in identifying and characterizing new tumor-suppressor genes.
The role of epigenetic domains such as super-enhancers in driving oncogene expression has become increasingly appreciated. However, whether tumor suppressors can be defined by a distinctive epigenetic signature in normal somatic cells remains unclear. Using integrative analysis of genome-wide epigenetic profiles and somatic mutations, Chen, Chen, and colleagues identified selective enrichment of exceptionally broad (wider than 4 kb), low-density peaks of histone H3 Lys4 trimethylation (H3K4me3) around the transcription start sites of highly expressed genes, including cell-identity genes and tumor-suppressor genes, but not housekeeping genes or oncogenes. This broad H3K4me3 signature correlated with the presence of many promoter-enriched epigenetic marks, suggesting that these promoter epigenetic marks exhibit similar extension. In particular, a strong correlation between broad H3K4me3 and increased transcription elongation was observed in multiple cell types. Furthermore, there was also a strong correlation between broad H3K4me3 and enhancer-associated marks, as well as transcription factor binding intensity, indicative of strong enhancer activity at these genes. Although a subset of genes with broad H3K4me3 peaks overlapped with genes associated with broad super-enhancers, tumor suppressors were enriched only in genes lacking super-enhancers, suggesting that broad H3K4me3 is a distinct epigenetic domain. Known pan-cancer tumor suppressors, including TP53 and PTEN, were enriched in broad H3K4me3 peaks that were highly conserved across most normal somatic cell types. Further analysis of these conserved peaks enabled the identification of putative tumor suppressors, and functional characterization confirmed that these candidate genes inhibited cancer cell growth. Compared with normal cells, conserved broad H3K4me3 peaks were shortened in various cancer cell lines and primary human lung and liver tumors, leading to reduced expression of tumor suppressors. These results identify broad H3K4me3 peaks as the first epigenetic signature enriched in tumor suppressors and suggest that this epigenetic marker may be useful in identifying tumor suppressor genes.