RNA Helicases DDX5 and DDX17 Dynamically Orchestrate Transcription, miRNA, and Splicing Programs in Cell Differentiation

•DDX5/DDX17 and hnRNP H/F regulate splicing by cooperating at GC-rich sequences•DDX5/DDX17 and hnRNP H/F control splicing programs in epithelial cells and myoblasts•A miRNA-mediated negative feedback loop downregulates DDX5/DDX17 in differentiation•DDX5/DDX17 control the expression of master differentiation transcription factors

SummaryThe RNA helicases DDX5 and DDX17 are members of a large family of highly conserved proteins that are involved in gene-expression regulation; however, their in vivo targets and activities in biological processes such as cell differentiation, which requires reprogramming of gene-expression programs at multiple levels, are not well characterized. Here, we uncovered a mechanism by which DDX5 and DDX17 cooperate with heterogeneous nuclear ribonucleoprotein (hnRNP) H/F splicing factors to define epithelial- and myoblast-specific splicing subprograms. We then observed that downregulation of DDX5 and DDX17 protein expression during myogenesis and epithelial-to-mesenchymal transdifferentiation contributes to the switching of splicing programs during these processes. Remarkably, this downregulation is mediated by the production of miRNAs induced upon differentiation in a DDX5/DDX17-dependent manner. Since DDX5 and DDX17 also function as coregulators of master transcriptional regulators of differentiation, we propose to name these proteins “master orchestrators” of differentiation that dynamically orchestrate several layers of gene expression.

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