Genomic characterization of Wilms' tumor suppressor 1 targets in nephron progenitor cells during kidney development

Author:

Hartwig Sunny12,Ho Jacqueline12,Pandey Priyanka12,MacIsaac Kenzie3,Taglienti Mary12,Xiang Michael4,Alterovitz Gil4,Ramoni Marco4,Fraenkel Ernest35,Kreidberg Jordan A.12

Affiliation:

1. Department of Medicine, Children's Hospital Boston; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA

2. Harvard Stem Cell Institute, Cambridge, MA 02138, USA

3. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

4. Harvard-MIT Division of Health Sciences and Technology and Children's Hospital Informatics Program, Boston, MA 02115, USA

5. Department of Biology and Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

Abstract

The Wilms' tumor suppressor 1 (WT1) gene encodes a DNA- and RNA-binding protein that plays an essential role in nephron progenitor differentiation during renal development. To identify WT1 target genes that might regulate nephron progenitor differentiation in vivo, we performed chromatin immunoprecipitation (ChIP) coupled to mouse promoter microarray (ChIP-chip) using chromatin prepared from embryonic mouse kidney tissue. We identified 1663 genes bound by WT1, 86% of which contain a previously identified, conserved, high-affinity WT1 binding site. To investigate functional interactions between WT1 and candidate target genes in nephron progenitors, we used a novel, modified WT1 morpholino loss-of-function model in embryonic mouse kidney explants to knock down WT1 expression in nephron progenitors ex vivo. Low doses of WT1 morpholino resulted in reduced WT1 target gene expression specifically in nephron progenitors, whereas high doses of WT1 morpholino arrested kidney explant development and were associated with increased nephron progenitor cell apoptosis, reminiscent of the phenotype observed in Wt1−/− embryos. Collectively, our results provide a comprehensive description of endogenous WT1 target genes in nephron progenitor cells in vivo, as well as insights into the transcriptional signaling networks controlled by WT1 that might direct nephron progenitor fate during renal development.

Publisher

The Company of Biologists

Subject

Developmental Biology,Molecular Biology

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