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CFIm-mediated alternative polyadenylation remodels cellular signaling and miRNA biogenesis

ABSTRACT: The mammalian cleavage factor I (CFIm) has been implicated in alternative polyadenylation (APA) in a broad range of contexts, from cancers to learning deficits and parasite infections. To determine how the CFIm expression levels are translated into these diverse phenotypes, we carried out a multi-omics analysis of cell lines in which the CFIm25 (NUDT21) or CFIm68 (CPSF6) subunits were either repressed by siRNA-mediated knockdown or over-expressed from stably integrated constructs. We established that more than 800 genes undergo coherent APA in response to changes in CFIm levels, and they cluster in distinct functional classes related to protein metabolism. The activity of the ERK pathway traces the CFIm concentration, and explains some of the fluctuations in cell growth and metabolism that are observed upon CFIm perturbations. Furthermore, multiple transcripts encoding proteins from the miRNA pathway are targets of CFIm-dependent APA. This leads to an increased biogenesis and repressive activity of miRNAs at the same time as some 3’ UTRs become shorter and presumably less sensitive to miRNA-mediated repression. Our study provides a first systematic assessment of a reference set of core APA targets, that respond to changes in CFIm protein subunit levels (CFIm25/CFIm68), and the elicited signalling pathways downstream of CFIm, to improve our understanding of the key role of CFIm in integrating RNA processing with other cellular activities.

ORGANISM(S): Homo sapiens

PROVIDER: GSE179630 | GEO | 2022/02/16

REPOSITORIES: GEO

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A jack of all trades and a master of some: remodeling of signaling pathways downstream of CFIm 3’ end processing factor

Project description:The mammalian cleavage factor I (CFIm) has been implicated in alternative polyadenylation (APA) in a broad range of contexts, from cancers to learning deficits and parasite infections. To uncover the molecular pathways that translate CFIm expression levels into these observed phenotypes, we carried out a multi-omics analysis of cell lines in which the CFIm25 (NUDT21) or CFIm68 (CPSF6) subunits were either repressed by siRNA-mediated knockdown or over-expressed from stably integrated constructs. We established that more than 600 genes exhibit CFIm-dependent APA, and they cluster in distinct functional classes related to protein metabolism. The activity of the ERK pathway traces the CFIm concentration, and explains some of the metabolic and proliferation changes induced by CFIm perturbations. Transcripts of miRNA pathway proteins are prominent targets of CFIm-dependent APA. This leads to increased miRNA biogenesis and repressive activity at the same time as 3’ UTRs become shorter upon CFIm depletion. Our study provides a first systematic assessment of the signalling pathways downstream of CFIm to improve our understanding of CFIm-dependent phenotypes.

2022-02-11 | PXD027034 | Pride

Interacting proteins of NUDT21 identified by IP-MS

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