Mitotic gene bookmarking by RUNX1 contributes to stabilization of the normal mammary epithelial phenotype

Loss of the RUNX1 transcription factor leads to epithelial-to-mesenchymal transition (EMT), but mechanisms by which RUNX1 stabilizes the mammary epithelial phenotype are not known. Here, we report RUNX1 gene bookmarking during mitosis as one of the key epigenetic mechanisms to convey regulatory information for coordinate control of mammary cell proliferation, growth, and identity through successive cell divisions. Genome-wide RUNX1 occupancy profiles for asynchronous, mitotically-enriched, and G1 breast epithelial cells reveal RUNX1 is retained during mitosis on RNA Pol I- (i.e., ribosomal RNA) and II-transcribed protein coding (e.g., HES1) and long non-coding RNA (e.g., NEAT1) genes controlling proliferation, growth, and mammary epithelial phenotype maintenance. Disruption of RUNX1 DNA binding and target gene occupancy alters cell morphology, global protein synthesis, and phenotype-related gene expression. Together, these findings demonstrate that RUNX1 mitotic bookmarking contributes to maintenance of the normal mammary epithelial phenotype. Compromising RUNX1 DNA binding initiates EMT, an essential first step in the onset of breast cancer.