Altered binding affinity of SIX1-Q177R correlates with enhanced WNT5A and WNT pathway effector expression in Wilms tumor

Author:

Stevenson Matthew J.1,Phanor Sabrina K.2,Patel Urvi1,Gisselbrecht Stephen S.2,Bulyk Martha L.23,O'Brien Lori L.1ORCID

Affiliation:

1. University of North Carolina at Chapel Hill 1 Department of Cell Biology and Physiology , , Chapel Hill, NC 27599 , USA

2. Brigham and Women's Hospital and Harvard Medical School 2 Division of Genetics, Department of Medicine , , Boston, MA 02115 , USA

3. Brigham and Women's Hospital and Harvard Medical School 3 Department of Pathology , , Boston, MA 02115 , USA

Abstract

ABSTRACT Wilms tumors present as an amalgam of varying proportions of tissues located within the developing kidney, one being the nephrogenic blastema comprising multipotent nephron progenitor cells (NPCs). The recurring missense mutation Q177R in NPC transcription factors SIX1 and SIX2 is most correlated with tumors of blastemal histology and is significantly associated with relapse. Yet, the transcriptional regulatory consequences of SIX1/2-Q177R that might promote tumor progression and recurrence have not been investigated extensively. Utilizing multiple Wilms tumor transcriptomic datasets, we identified upregulation of the gene encoding non-canonical WNT ligand WNT5A in addition to other WNT pathway effectors in SIX1/2-Q177R mutant tumors. SIX1 ChIP-seq datasets from Wilms tumors revealed shared binding sites for SIX1/SIX1-Q177R within a promoter of WNT5A and at putative distal cis-regulatory elements (CREs). We demonstrate colocalization of SIX1 and WNT5A in Wilms tumor tissue and utilize in vitro assays that support SIX1 and SIX1-Q177R activation of expression from the WNT5A CREs, as well as enhanced binding affinity within the WNT5A promoter that may promote the differential expression of WNT5A and other WNT pathway effectors associated with SIX1-Q177R tumors.

Funder

University of North Carolina

National Human Genome Research Institute

National Cancer Institute

National Institute of General Medical Sciences

Publisher

The Company of Biologists

Subject

General Biochemistry, Genetics and Molecular Biology,Immunology and Microbiology (miscellaneous),Medicine (miscellaneous),Neuroscience (miscellaneous)

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1. Synergistic modelling of human disease;Disease Models & Mechanisms;2024-02-01

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