METTL3-dependent m6A RNA methylation suppresses aberrant mammary epithelial differentiation and neoplastic transformation
Abstract
The mechanisms underlying sustained proliferation and aberrant cellular plasticity that drive early breast tumorigenesis remain unclear. Using CRISPR knockout (KO) screens, we systematically characterized the regulators of cellular fitness in the normal mammary epithelium. We found that loss of METTL3 stimulates mammary epithelial proliferation and reprograms gene expression in an m6A methyltransferase-dependent manner. Single-cell analysis in normal breast organoids revealed that METTL3 ablation causes disruption of the mammary cellular hierarchy through increased aberrant luminal differentiation. Mechanistically, METTL3 loss reduces RNA m6A modification of transcribed transposable elements leading to their increased expression and upregulation of interferon-STAT signaling. This inflammatory response leads to cross talk between STAT and GATA3 transcription factors, resulting in transcriptional activation of luminal genes in the mammary epithelium. These findings identify a cell-intrinsic epigenetic loop contributing to mammary epithelial differentiation and highlight a potential role of loss of METTL3-dependent m6A modification during neoplastic transformation.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (22)
Yihao Li
Department of Medical Oncology, Dana-Farber Cancer Institute
Xintao Qiu
Department of Medical Oncology, Dana-Farber Cancer Institute
Zachary Sandusky
Department of Medical Oncology, Dana-Farber Cancer Institute
Kaitlin Tagliaferri
Ludwig Center at Harvard, Harvard Medical School
Rong Li
Xin Yang
Tao Zhang
Shimeng Liu
Department of Medical Oncology, Dana-Farber Cancer Institute
Pengze Yan
Department of Medical Oncology, Dana-Farber Cancer Institute
Feng Lu
Department of Medical Oncology, Dana-Farber Cancer Institute
Marcus Jones
Tengfei Xiao
Department of Medical Oncology, Dana-Farber Cancer Institute
Wei Li
Seth Goldman
Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School
Jie Cui
Shanghai Sci-Tech Inno Center for Infection and Immunity, National Medical Center for Infectious Diseases, Huashan Hospital, Institute of Infection and Health, Fudan University
Kornelia Polyak
Department of Medical Oncology, Dana-Farber Cancer Institute
X. Shirley Liu
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute
Henry W. Long
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute
Richard I. Gregory
Department of Molecular, Cell, and Cancer Biology, UMass Chan Medical School
Karen Adelman
Ludwig Center at Harvard, Harvard Medical School
Jennifer M. Rosenbluth
Department of Medical Oncology, Dana-Farber Cancer Institute
Myles Brown
Department of Medical Oncology, Dana-Farber Cancer Institute