Paraspeckle-independent co-transcriptional regulation of nuclear microRNA biogenesis by SFPQ
Caroline Thivierge,
Maxime Bellefeuille,
Sarah-Slim Diwan,
Boris J.A. Dyakov,
Rania Leventis,
Gabrielle Perron,
Hamed S. Najafabadi,
Simon-Pierre Gravel,
Anne-Claude Gingras,
Thomas F. Duchaine
Affiliations
Caroline Thivierge
Rosalind and Morris Goodman Cancer Institute, McGill Centre for RNA Sciences & Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada
Maxime Bellefeuille
Rosalind and Morris Goodman Cancer Institute, McGill Centre for RNA Sciences & Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada
Sarah-Slim Diwan
Rosalind and Morris Goodman Cancer Institute, McGill Centre for RNA Sciences & Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada
Boris J.A. Dyakov
Lunenfeld-Tanenbaum Research Institute, Sinai Health System & Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1X5, Canada
Rania Leventis
Rosalind and Morris Goodman Cancer Institute, McGill Centre for RNA Sciences & Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada
Gabrielle Perron
McGill Genome Centre & Department of Human Genetics, McGill University, Montréal, QC H3A 0G1, Canada
Hamed S. Najafabadi
McGill Genome Centre & Department of Human Genetics, McGill University, Montréal, QC H3A 0G1, Canada
Simon-Pierre Gravel
Faculté de Pharmacie, Université de Montréal, Montréal, QC H3T 1J4, Canada
Anne-Claude Gingras
Lunenfeld-Tanenbaum Research Institute, Sinai Health System & Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1X5, Canada
Thomas F. Duchaine
Rosalind and Morris Goodman Cancer Institute, McGill Centre for RNA Sciences & Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada; Corresponding author
Summary: MicroRNAs (miRNAs) play crucial roles in physiological functions and disease, but the regulation of their nuclear biogenesis remains poorly understood. Here, BioID on Drosha, the catalytic subunit of the microprocessor complex, reveals its proximity to splicing factor proline- and glutamine (Q)-rich (SFPQ), a multifunctional RNA-binding protein (RBP) involved in forming paraspeckle nuclear condensates. SFPQ depletion impacts both primary and mature miRNA expression, while other paraspeckle proteins (PSPs) or the paraspeckle scaffolding RNA NEAT1 do not, indicating a paraspeckle-independent role. Comprehensive transcriptomic analyses show that SFPQ loss broadly affects RNAs and miRNA host gene (HG) expression, influencing both their transcription and the stability of their products. Notably, SFPQ protects the oncogenic miR-17∼92 polycistron from degradation by the nuclear exosome targeting (NEXT)-exosome complex and is tightly linked with its overexpression across a broad variety of cancers. Our findings reveal a dual role for SFPQ in regulating miRNA HG transcription and stability, as well as its significance in cancers.
