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Loss of METTL3 potentiates transposable element expression and drives inflammation-induced cell plasticity in the mammary epithelium [RNA-seq]

ABSTRACT: Sustained proliferation and aberrant cellular plasticity are the hallmarks of breast premalignancy, yet the mechanisms driving this process remain unclear. Using CRISPR knockout screens, we systematically characterized the regulators of cellular fitness in the normal mammary epithelium. We found that loss of RNA methyltransferase METTL3 initiates mammary epithelial proliferation and reprograms gene expression, which depends on its catalytic activity. Single-cell analysis in normal breast organoids revealed that METTL3 ablation causes disruption of the mammary cellular hierarchy through increased aberrant luminal differentiation. Mechanically, METTL3 loss reduces the RNA m6A modification of transcribed transposable elements leading to their increased expression and upregulating interferon-STAT signaling. This inflammatory response leads to the crosstalk 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 plasticity and highlight a potential role of METTL3-dependent m6A modification during neoplastic transformation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE280918 | GEO | 2025/11/01

REPOSITORIES: GEO

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Loss of METTL3 potentiates transposable element expression and drives inflammation-induced cell plasticity in the mammary epithelium [ChIP-seq]

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Loss of METTL3 potentiates transposable element expression and drives inflammation-induced cell plasticity in the mammary epithelium [ATAC-seq]

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Project description:In this study we identify Mettl3, an m6A RNA modification writer, as a critical regulator for terminating naM-CM-/ve pluripotency and a positive maintainer of primed pluripotency in vitro and in vivo. Remarkably, Mettl3 knockout pre-implantation epiblasts and naM-CM-/ve ES cells, entirely lack m6A on coding mRNAs and are viable. Yet, they fail to adequately terminate the naM-CM-/ve pluripotent state, and subsequently undergo aberrant priming and early lineage commitment at the post-implantation stage. A comprehensive functional and genomic analysis involving profiling of m6A, RNA transcription and translation in Mettl3 wild-type and knockout pluripotent and differentiated cells, identified m6A as a critical determinant that destabilizes secondary naM-CM-/ve specific pluripotency genes Esrrb, Klf4 and Nanog, and restrains their transcript stability and translation efficiency. In summary, our findings provide for the first time evidence for a critical role for an mRNA epigenetic modification in early mammalian development in vivo, and identify a mechanism that functionally regulates mouse naM-CM-/ve and primed pluripotency in an opposing manner. m6A-seq was measured from total RNA in mouse embryonic stem cells (ESCs), embroid bodies (EBs) and embronic fibroblasts (MEF). 3 biological replicates are available from BVSC ESC line and EBs, and two biological replicates are available for MEFs. Each sample consist of IP to m6A and control input

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