Differential regulation of MYC expression by in human and mouse kidneys: phenotypic implications for recessive polycystic kidney disease

Naoe Harafuji, Center for Translational Research, Children's National Hospital, Washington, DC, United States.
Chaozhe Yang, Center for Translational Research, Children's National Hospital, Washington, DC, United States.
Maoqing Wu, Center for Translational Research, Children's National Hospital, Washington, DC, United States.
Girija Thiruvengadam, Center for Translational Research, Children's National Hospital, Washington, DC, United States.
Heather Gordish-Dressman, Center for Translational Research, Children's National Hospital, Washington, DC, United States.
R Griffin Thompson, Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, AL, United States.
P Darwin Bell, Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, AL, United States.
Avi Z. Rosenberg, Department of Pathology, Johns Hopkins University, Baltimore, MD, United States.
Claudia Dafinger, Department of Pediatrics and Center for Molecular Medicine, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany.
Max C. Liebau, Department of Pediatrics, Center for Family Health, Center for Rare Diseases and Center for Molecular Medicine, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany.
Zsuzsanna Bebok, Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, AL, United States.
Ljubica Caldovic, Center for Genetic Medicine Research, Children's National Hospital, Washington, DC, United States.
Lisa M. Guay-Woodford, Center for Translational Research, Children's National Hospital, Washington, DC, United States.

Document Type

Journal Article

Publication Date

1-1-2023

Journal

Frontiers in cell and developmental biology

Volume

11

DOI

10.3389/fcell.2023.1270980

Keywords

ARPKD; Cys1; FPC; MYC; PKHD1; cystin

Abstract

Autosomal recessive polycystic kidney disease (ARPKD; MIM#263200) is a severe, hereditary, hepato-renal fibrocystic disorder that leads to early childhood morbidity and mortality. Typical forms of ARPKD are caused by pathogenic variants in the gene, which encodes the fibrocystin/polyductin (FPC) protein. MYC overexpression has been proposed as a driver of renal cystogenesis, but little is known about MYC expression in recessive PKD. In the current study, we provide the first evidence that MYC is overexpressed in kidneys from ARPKD patients and confirm that MYC is upregulated in cystic kidneys from mutant mice. In contrast, renal MYC expression levels were not altered in several mutant mice that lack a significant cystic kidney phenotype. We leveraged previous observations that the carboxy-terminus of mouse FPC (FPC-CTD) is proteolytically cleaved through Notch-like processing, translocates to the nucleus, and binds to double stranded DNA, to examine whether the FPC-CTD plays a role in regulating transcription. Using immunofluorescence, reporter gene assays, and ChIP, we demonstrate that both human and mouse FPC-CTD can localize to the nucleus, bind to the P1 promoter, and activate expression. Interestingly, we observed species-specific differences in FPC-CTD intracellular trafficking. Furthermore, our informatic analyses revealed limited sequence identity of FPC-CTD across vertebrate phyla and database queries identified temporal differences in / and / expression patterns in mouse and human kidneys. Given that cystin, the gene product, is a negative regulator of transcription, these temporal differences in gene expression could contribute to the relative renoprotection from cystogenesis in -deficient mice. Taken together, our findings provide new mechanistic insights into differential mFPC-CTD and hFPC-CTD regulation of MYC expression in renal epithelial cells, which may illuminate the basis for the phenotypic disparities between human patients with pathogenic variants and -mutant mice.

Department

Genomics and Precision Medicine

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