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Hum Mol Genet. 2018 Nov 1. doi: 10.1093/hmg/ddy379. [Epub ahead of print]

C-MYC is a regulator ofthe PKD1 gene and PC1-induced pathogenesis.

Author information

1
Institut de recherches cliniques de Montréal, Molecular Genetics and Development, Faculté de Médecine de L'Université de Montréal, Montréal, Québec, Canada.

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is among the most common monogenic disordersmainly associated with Pkd1/Pc1 mutations. We show herein that renal regulation in Pc1 dosage-reduced and -increased mouse models converge toward stimulation ofc-Myc expression along with β-catenin, delineating c-Myc as a key Pkd1 node in cystogenesis. Enhanced renal c-Myc-induced ADPKDin SBM transgenic mice lead conversely to striking upregulation of Pkd1/Pc1 expressionand β-catenin activation, lending credence forreciprocal 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 bindingat 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 thePkd1 regulatory region probably opens chromatin to stimulate transcription. A similar transcriptional activation by c-Myc is also likely operant onendogenous human PKD1genefrom 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 studydetermined adual 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 alsoprevail in human ADPKD.

PMID:
30388220
PMCID:
PMC6381314
[Available on 2020-03-01]
DOI:
10.1093/hmg/ddy379

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