Inhibition of the RUNX1-CBFβ transcription factor complex compromises mammary epithelial cell identity: a phenotype potentially stabilized by mitotic gene bookmarking

Abstract

RUNX1 has recently been shown to play an important role in determination of mammary epithelial cell identity. However, mechanisms by which loss of the RUNX1 transcription factor in mammary epithelial cells leads to epithelial-to-mesenchymal transition (EMT) are not known. Here, we report that interaction between RUNX1 and its heterodimeric partner CBFβ is essential for sustaining mammary epithelial cell identity. Disruption of RUNX1-CBFβ interaction, DNA binding, and association with mitotic chromosomes alters cell morphology, global protein synthesis, and phenotyperelated gene expression. During interphase, RUNX1 is organized as punctate, predominantly nuclear, foci that are dynamically redistributed during mitosis, with a subset localized to mitotic chromosomes. Genome-wide RUNX1 occupancy profiles for asynchronous, mitotically enriched, and early G1 breast epithelial cells reveal RUNX1 associates with RNA Pol II-transcribed protein coding and long non-coding RNA genes and RNA Pol I-transcribed ribosomal genes critical for mammary epithelial proliferation, growth, and phenotype maintenance. A subset of these genes remains occupied by the protein during the mitosis to G1 transition. Together, these findings establish that the RUNX1-CBFβ complex is required for maintenance of the normal mammary epithelial phenotype and its disruption leads to EMT. Importantly, our results suggest, for the first time, that RUNX1 mitotic bookmarking of a subset of epithelial-related genes may be an important epigenetic mechanism that contributes to stabilization of the mammary epithelial cell identity.

Hyperglycemia Induces Trained Immunity in Macrophages and Their Precursors and Promotes Atherosclerosis

“…For instance, disruption of the RUNX1 interaction during mitosis leads to epithelial-to-mesenchymal transition. 64 Pharmacological inhibition of RUNX1 with Ro5-3335 normalized the altered inflammatory gene expression associated with in vitro hyperglycemia-induced trained immunity. The targeted intervention against RUNX1 provides further evidence of the involvement of RUNX1 in the downstream effects of hyperglycemia-induced trained immunity in macrophages.…”

Aberrations of Chromosomes 1 and 16 in Breast Cancer: A Framework for Cooperation of Transcriptionally Dysregulated Genes

“…Indeed, a role for CBFB in the suppression of breast cancer has recently emerged, and it has been reported that nuclear CBFB/RUNX1 complex represses the oncogenic NOTCH signaling pathway in breast cancer [ 98 ]. Moreover, an efficient function of the CBFB/RUNX1 complex is necessary for the maintenance of the normal mammary epithelial phenotype [ 99 ]. In particular, the CBFB/RUNX1 complex represses NOTCH3 [ 98 ], and this observation establishes another interesting link among the underexpression of a 16q gene (CBFB)—the overexpression of 1q-located gamma-secretase component and the pathway “NOTCH3 Activation and Transmission of Signal to the Nucleus,” as described in previous paragraphs.…”

Epigenetic and transcriptome responsiveness to ER modulation by tissue selective estrogen complexes in breast epithelial and breast cancer cells

“…The H3K4ac responsive gene promoter regions not bound by ERα (clusters 1 and 2) correspond to genes associated with cell cycle regulation, DNA metabolic processes and mitotic checkpoints ( Fig 4E ; TSS). Genes that annotate to enhancer regions (cluster 3) are enriched with signaling pathways of validated estrogen networks and include several estrogen-related pathways in addition to transcriptional regulation by RUNX1, a pathway linked to breast cancer and tumor suppression [ 47 – 51 ]. Of significance, a role for RUNX1 in mediating ERα tethering versus direct genomic recruitment to estrogen response elements has been reported [ 52 ].…”