Genome-Wide Analysis of Wilms' Tumor 1-Controlled Gene Expression in Podocytes Reveals Key Regulatory Mechanisms

J Am Soc Nephrol. 2015 Sep;26(9):2097-104. doi: 10.1681/ASN.2014090940. Epub 2015 Jan 30.

Abstract

The transcription factor Wilms' tumor suppressor 1 (WT1) is key to podocyte development and viability; however, WT1 transcriptional networks in podocytes remain elusive. We provide a comprehensive analysis of the genome-wide WT1 transcriptional network in podocytes in vivo using chromatin immunoprecipitation followed by sequencing (ChIPseq) and RNA sequencing techniques. Our data show a specific role for WT1 in regulating the podocyte-specific transcriptome through binding to both promoters and enhancers of target genes. Furthermore, we inferred a podocyte transcription factor network consisting of WT1, LMX1B, TCF21, Fox-class and TEAD family transcription factors, and MAFB that uses tissue-specific enhancers to control podocyte gene expression. In addition to previously described WT1-dependent target genes, ChIPseq identified novel WT1-dependent signaling systems. These targets included components of the Hippo signaling system, underscoring the power of genome-wide transcriptional-network analyses. Together, our data elucidate a comprehensive gene regulatory network in podocytes suggesting that WT1 gene regulatory function and podocyte cell-type specification can best be understood in the context of transcription factor-regulatory element network interplay.

Keywords: gene expression; gene transcription; genetics and development; glomerular disease; glomerulus; podocyte.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Chromatin Immunoprecipitation
  • Forkhead Transcription Factors / genetics
  • Gene Expression Regulation*
  • Genomics
  • LIM-Homeodomain Proteins / genetics
  • MafB Transcription Factor / genetics
  • Mice
  • Podocytes*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Repressor Proteins / genetics*
  • Sequence Analysis, DNA
  • Sequence Analysis, RNA
  • Signal Transduction / genetics*
  • Transcription Factors / genetics
  • Transcriptome*
  • WT1 Proteins

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Forkhead Transcription Factors
  • LIM homeobox transcription factor 1 beta
  • LIM-Homeodomain Proteins
  • MafB Transcription Factor
  • Mafb protein, mouse
  • Repressor Proteins
  • Tcf21 protein, mouse
  • Transcription Factors
  • WT1 Proteins
  • WT1 protein, mouse
  • Hippo protein, mouse
  • Protein-Serine-Threonine Kinases