c-Myc is a regulator of the PKD1 gene and PC1-induced pathogenesis.

Autosomal dominant polycystic kidney disease (ADPKD) is among the most common monogenic disorders mainly associated with PKD1/PC1 mutations. We show herein that renal regulation in Pc1 dosage-reduced and -increased mouse models converge toward stimulation of c-Myc expression along with ß-catenin, delineating c-Myc as a key Pkd1 node in cystogenesis. Enhanced renal c-Myc-induced ADPKD in SBM transgenic mice lead conversely to striking upregulation of Pkd1/Pc1 expression and ß-catenin activation, lending credence for reciprocal crosstalk between c-Myc and Pc1. In adult SBM kidneys, c-Myc is strongly enriched on Pkd1 promoter with RNA pol II, consistent with Pkd1 upregulation during cystogenesis. Similar c-Myc direct binding at birth uncovers an equivalent role on Pkd1 regulation during renal developmental program. Concurrent with enriched c-Myc binding, recruitment of active chromatin modifying co-factors by c-Myc at the Pkd1 regulatory region probably opens chromatin to stimulate transcription. A similar transcriptional activation by c-Myc is also likely operant on endogenous human PKD1 gene from our transactivation analysis in response to human c-MYC upregulation. Genetic ablation of c-Myc in Pc1-reduced and -increased mouse models significantly attenuates cyst growth, proliferation and PKD progression. Our study determined a dual role for c-Myc, as a major contributor in Pc1-induced cystogenesis and in a feed-forward regulatory Pkd1-c-Myc loop mechanism that may also prevail in human ADPKD.