Institute of Information Science, Academia Sinica

Cell plasticity is the ability of cancer cells to transition between distinct epigenetic cell states and underlies tumor cell heterogeneity, which promotes disease progression and therapeutic resistance. During breast cancer, the epigenetic mark H4K20me3 is depleted in aggressive basal-like/triple-negative subtypes compared to less aggressive luminal subtypes, and reduced levels of H4K20me3 in primary breast tumors are prognostic of a poor outcome. H4K20me3 is a feature of constitutive heterochromatin with roles in DNA replication, telomere/centromere stability, and 3D-chromatin organization; however, H4K20me3 has also been implicated as a potential transcriptional regulator suggesting it might contribute to phenotypic plasticity. We find that the genomic distribution of H4K20me3 distinguishes luminal and basal breast cell subtypes and lineage-defining H4K20me3-marked regions are associated with features of active enhancers. Depletion of H4K20me3 in immortalized breast epithelial cells promotes plasticity along the EMT axis, unleashing a mesenchymal-driving transcriptional program and promoting invasive behavior. Upon TGF-induced transition to the mesenchymal state, H4K20me3 accumulates at active super enhancers where it corresponds with the expression of nearby genes. Together, these studies identify a novel role for H4K20me3 in suppressing lineage plasticity at active enhancers.