METTL3-dependent m6A RNA methylation suppresses aberrant mammary epithelial differentiation and neoplastic transformation
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.
Authors
- Xin Yang (ORCID: https://orcid.org/0000-0001-6632-9608)
- Seth Goldman (ORCID: https://orcid.org/0000-0001-5096-3778)
- Kornélia Polyák (ORCID: https://orcid.org/0000-0002-5964-0382)
- M. Jones (ORCID: https://orcid.org/0000-0003-1344-5263)
- X. Shirley Liu (ORCID: https://orcid.org/0000-0001-6710-2771)
- Zachary M. Sandusky (ORCID: https://orcid.org/0000-0001-7717-2546)
- Jie Cui (ORCID: https://orcid.org/0000-0001-8176-9951)
- Tengfei Xiao (ORCID: https://orcid.org/0000-0001-5704-9882)
- Myles A Brown (ORCID: https://orcid.org/0000-0002-8213-1658)
- Xintao Qiu (ORCID: https://orcid.org/0000-0002-8560-7017)
- Feng Gui Lu (ORCID: https://orcid.org/0000-0001-9064-7964)
- Richard I. Gregory (ORCID: https://orcid.org/0000-0001-8090-8673)
- Henry W. Long (ORCID: https://orcid.org/0000-0001-6849-6629)
- Pengze Yan (ORCID: https://orcid.org/0000-0001-8142-0944)
- Shimeng Liu (ORCID: https://orcid.org/0000-0002-4369-4589)
- Karen Adelman
- Wei Li (ORCID: https://orcid.org/0000-0001-9931-5990)
- Tao Zhang (ORCID: https://orcid.org/0000-0003-1048-4443)
- Yihao Li (ORCID: https://orcid.org/0000-0003-1900-8099)
- Rong Li (ORCID: https://orcid.org/0000-0001-7266-0241)
- Kaitlin Tagliaferri
Institutions
- Children's National (US)
- Harvard University (US)
- University of Massachusetts Chan Medical School (US)
- University of California, San Francisco (US)
- George Washington University (US)
- Genetic Resources Center (JP)
- Boston VA Research Institute (US)
- Dana-Farber Cancer Institute (US)
- Huashan Hospital (CN)
- UMass Memorial Medical Center (US)
- UCSF Helen Diller Family Comprehensive Cancer Center (US)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-11-11
- DOI
- https://doi.org/10.1073/pnas.2514643122
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Susan G. Komen for the Cure
- Eli Lilly and Company
- Sanofi
- FibroGen
- Dana-Farber Cancer Institute
- Dana-Farber/Harvard Cancer Center
- Astellas Pharma
- Ludwig Center at Harvard
- National Cancer Institute