title: Genome-Wide Analysis of Wilms' Tumor 1-Controlled Gene Expression in Podocytes Reveals Key Regulatory Mechanisms.
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.
authors: Division of Nephrology, Department of Medicine and Department II of Internal Medicine and Center for Molecular Medicine Cologne and.
authors: Martin
authors: M
authors: Kann
authors: Division of Nephrology, Department of Medicine and.
authors: Sandrine
authors: S
authors: Ettou
authors: Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts;
authors: Youngsook L
authors: YL
authors: Jung
authors: Department II of Internal Medicine and Center for Molecular Medicine Cologne and.
authors: Maximilian O
authors: MO
authors: Lenz
authors: Division of Nephrology, Department of Medicine and.
authors: Mary E
authors: ME
authors: Taglienti
authors: Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Informatics Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;
authors: Peter J
authors: PJ
authors: Park
authors: Department II of Internal Medicine and Center for Molecular Medicine Cologne and Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases, Cologne, Germany; and Systems Biology of Ageing Cologne, University of Cologne, Cologne, Germany;
authors: Bernhard
authors: B
authors: Schermer
authors: Department II of Internal Medicine and Center for Molecular Medicine Cologne and Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases, Cologne, Germany; and Systems Biology of Ageing Cologne, University of Cologne, Cologne, Germany; jordan.kreidberg@childrens.harvard.edu thomas.benzing@uk-koeln.de.
authors: Thomas
authors: T
authors: Benzing
authors: Division of Nephrology, Department of Medicine and Harvard Stem Cell Institute, Cambridge, Massachusetts jordan.kreidberg@childrens.harvard.edu thomas.benzing@uk-koeln.de.
authors: Jordan A
authors: JA
authors: Kreidberg
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D051858:Forkhead Transcription Factors / Q000235:genetics; D005786:Gene Expression Regulation; D023281:Genomics; D000090683:Hippo Signaling Pathway; D060850:LIM-Homeodomain Proteins / Q000235:genetics; D051258:MafB Transcription Factor / Q000235:genetics; D051379:Mice; D050199:Podocytes; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D059467:Transcriptome; D025721:WT1 Proteins
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051858:Forkhead Transcription Factors; D060850:LIM-Homeodomain Proteins; D051258:MafB Transcription Factor; D017346:Protein Serine-Threonine Kinases; D012097:Repressor Proteins; D014157:Transcription Factors; D025721:WT1 Proteins; C112149:LIM homeobox transcription factor 1 beta; C490406:Mafb protein, mouse; C112923:Tcf21 protein, mouse; C000602896:WT1 protein, mouse
keywords: gene expression; gene transcription; genetics and development; glomerular disease; glomerulus; podocyte
references: Pediatrics. 2012 Jun;129(6):e1621-5
references: 22585769
references: Nature. 2012 Aug 2;488(7409):116-20
references: 22763441
references: J Am Soc Nephrol. 2011 Jul;22(7):1286-96
references: 21719793
references: PLoS Genet. 2011 Dec;7(12):e1002404
references: 22216009
references: Nature. 2012 Sep 6;489(7414):75-82
references: 22955617
references: J Am Soc Nephrol. 2014 Nov;25(11):2459-70
references: 24904088
references: Nat Commun. 2014;5:4444
references: 25031030
references: Gene Regul Syst Bio. 2013 Nov 04;7:139-52
references: 24250222
references: Genome Res. 2012 Sep;22(9):1813-31
references: 22955991
references: Curr Biol. 2001 Nov 13;11(22):1805-9
references: 11719225
references: PLoS One. 2009;4(4):e5103
references: 19337366
references: Front Biosci. 2007;12:2279-90
references: 17127464
references: Clin J Am Soc Nephrol. 2010 Sep;5(9):1655-62
references: 20595692
references: PLoS Genet. 2013 Mar;9(3):e1003380
references: 23555292
references: J Am Soc Nephrol. 2004 Nov;15(11):2851-6
references: 15504938
references: Development. 2010 Apr;137(7):1189-203
references: 20215353
references: J Biol Chem. 2013 Jun 14;288(24):17057-62
references: 23667252
references: Cell. 2013 Aug 29;154(5):1047-59
references: 23954413
references: Clin J Am Soc Nephrol. 2014 Jun 6;9(6):1109-16
references: 24742477
references: Nat Rev Nephrol. 2013 Jun;9(6):328-36
references: 23609563
references: J Am Soc Nephrol. 2013 Nov;24(11):1830-48
references: 23990680
references: J Am Soc Nephrol. 2014 Nov;25(11):2546-57
references: 24722438
references: J Clin Invest. 2002 Apr;109(8):1065-72
references: 11956244
references: Mol Cell Biol. 2013 Sep;33(17):3461-72
references: 23816881
references: Nature. 2009 May 7;459(7243):108-12
references: 19295514
references: Nature. 2011 Jun 9;474(7350):179-83
references: 21654799
references: J Am Soc Nephrol. 2014 Dec;25(12):2764-77
references: 24854274
references: Dev Cell. 2011 Sep 13;21(3):559-74
references: 21871842
references: Kidney Int. 2013 Jun;83(6):1052-64
references: 23364521
references: J Am Soc Nephrol. 2015 Mar;26(3):677-91
references: 25071087