Multilayer and MATR3-dependent regulation of mRNAs maintains pluripotency in human induced pluripotent stem cells

Daniele Pollini; Rosa Loffredo; Federica Maniscalco; Marina Cardano; Mariachiara Micaelli; Isabelle Bonomo; Nausicaa Valentina Licata; Daniele Peroni; Weronika Tomaszewska; Annalisa Rossi; Valeria Crippa; Erik Dassi; Gabriella Viero; Alessandro Quattrone; Angelo Poletti; Luciano Conti; Alessandro Provenzani

doi:10.1016/j.isci.2021.102197

Multilayer and MATR3-dependent regulation of mRNAs maintains pluripotency in human induced pluripotent stem cells

iScience. 2021 Feb 16;24(3):102197. doi: 10.1016/j.isci.2021.102197. eCollection 2021 Mar 19.

Authors

Daniele Pollini¹, Rosa Loffredo¹, Federica Maniscalco^{1

2}, Marina Cardano³, Mariachiara Micaelli¹, Isabelle Bonomo¹, Nausicaa Valentina Licata¹, Daniele Peroni⁴, Weronika Tomaszewska¹, Annalisa Rossi¹, Valeria Crippa⁵, Erik Dassi¹, Gabriella Viero², Alessandro Quattrone¹, Angelo Poletti⁵, Luciano Conti¹, Alessandro Provenzani¹

Affiliations

¹ Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy.
² Institute of Biophysics, CNR, Trento, Italy.
³ Cell Technology Core Facility, Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy.
⁴ Mass Spectrometry Core Facility, Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy.
⁵ Laboratorio di Biologia Applicata, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.

Abstract

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 key pluripotency regulators' expression levels, including OCT4, NANOG, and LIN28A by pleiotropic mechanisms. MATR3 binds to the OCT4 and YTHDF1 promoters favoring their expression. YTHDF1, in turn, binds the m6A-modified OCT4 mRNA. Furthermore, MATR3 is recruited on ribosomes and controls pluripotency regulating the translation of specific transcripts, including NANOG and LIN28A, by direct binding and favoring their stabilization. These results show that MATR3 orchestrates the pluripotency circuitry by regulating the transcription, translational efficiency, and epitranscriptome of specific transcripts.

Keywords: cellular neuroscience; molecular biology; stem cells research.