Inhibition of the RUNX1-CBFβ transcription factor complex compromises mammary epithelial cell identity: a phenotype potentially stabilized by mitotic gene bookmarking
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Joshua T. Rose1,*, Eliana Moskovitz1,*, Joseph R. Boyd1, Jonathan A. Gordon1, Nicole A. Bouffard2, Andrew J. Fritz1, Anuradha Illendula3, John H. Bushweller3, Jane B. Lian1, Janet L. Stein1, Sayyed K. Zaidi1 and Gary S. Stein1
1 Department of Biochemistry and University of Vermont Cancer Center, Robert Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA
2 Microscopy Imaging Center at the Robert Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA
3 Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA
* These authors contributed equally to this work
|Gary S. Stein,||email:||[email protected]|
|Sayyed K. Zaidi,||email:||[email protected]|
Keywords: mammary epithelial phenotype; epithelial phenotype; RUNX1; CBFβ; mitotic gene bookmarking
Received: May 02, 2020 Accepted: May 20, 2020 Published: June 30, 2020
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 phenotype-related 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.
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