MATR3-Dependent Multilayer Regulation of OCT4, NANOG and LIN28A is Essential for the Maintenance of the Human Pluripotency

Matrin3 (MATR3) is a nuclear RNA/DNA binding protein that plays pleiotropic roles in gene expression regulation by directly stabilizing target RNAs and supporting the activity of transcription factors by modulating chromatin architecture. MATR3 is involved in the differentiation of neural cells and, here, we elucidate its critical functions in regulating pluripotent circuits in human induced Pluripotent Stem Cells (hiPSCs). MATR3 downregulation affects hiPSCs differentiation potential by altering the expression level of key pluripotency regulators, including OCT4, NANOG, and LIN28A. MATR3 is recruited with specific initiation factors on ribosomes, and controls pluripotency regulating the translation of specific transcripts including NANOG and LIN28A by direct binding and favouring their stabilization. Moreover, MATR3 stimulates the expression of YTHDF1 , which, in turn, binds the m6A-modified OCT4 mRNA. These results show that MATR3 orchestrates the pluripotency circuitry by modulating the translational efficiency and regulating the epitranscriptome of specific transcripts.