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An Integrated Genome Screen Identifies the Wnt Signaling Pathway As a Major Target of WT1

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An Integrated Genome Screen Identifies the Wnt Signaling Pathway As a Major Target of WT1 An integrated genome screen identifies the Wnt signaling pathway as a major target of WT1 Marianne K.-H. Kima,b, Thomas J. McGarryc, Pilib O´ Broind, Jared M. Flatowb, Aaron A.-J. Goldend, and Jonathan D. Lichta,b,1 aDivision of Hematology/Oncology and cFeinberg Cardiovascular Research Institute, Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; bRobert H. Lurie Cancer Center, Northwestern University, Chicago, IL 60611; and dDepartment of Information Technology, National University of Ireland, Galway, Republic of Ireland Edited by Peter K. Vogt, The Scripps Research Institute, La Jolla, CA, and approved May 18, 2009 (received for review February 12, 2009) WT1, a critical regulator of kidney development, is a tumor suppressor control. A first generation of in vitro cotransfection and DNA for nephroblastoma but in some contexts functions as an oncogene. binding assays have given way to more biologically relevant exper- A limited number of direct transcriptional targets of WT1 have been iments where manipulation of WT1 levels has been accompanied identified to explain its complex roles in tumorigenesis and organo- by examination of candidate or global gene expression. Classes of genesis. In this study we performed genome-wide screening for direct WT1 targets thus identified consist of inducers of differentiation, WT1 targets, using a combination of ChIP–ChIP and expression arrays. regulators of cell growth and modulators of cell death. WT1 target Promoter regions bound by WT1 were highly G-rich and resembled genes include CDKN1A (22), a negative regulator of the cell cycle; the sites for a number of other widely expressed transcription factors AREG (23), a facilitator of kidney differentiation; WNT4 (24), a such as SP1, MAZ, and ZNF219. Genes directly regulated by WT1 were stimulator of renal development; and SPRY1 (25), a critical intra- implicated in MAPK signaling, axon guidance, and Wnt pathways. cellular regulator of receptor tyrosine kinase signaling and kidney Among directly bound and regulated genes by WT1, nine were development. Examination of gene expression in WT1 null and identified in the Wnt signaling pathway, suggesting that WT1 mod- WT1 replete Wilms tumor specimens identified a gene (IFI16) not ulates a subset of Wnt components and responsive genes by direct normally regulated or even expressed in the same subcellular binding. To prove the biological importance of the interplay between compartment as WT1 but regulated in a pathological manner in WT1 and Wnt signaling, we showed that WT1 blocked the ability of tumors (21). Wnt8 to induce a secondary body axis during Xenopus embryonic To comprehensively identify WT1 target genes we manipulated development. WT1 inhibited TCF-mediated transcription activated by WT1 levels in a Wilms tumor cell line by conditional overexpression Wnt ligand, wild type and mutant, stabilized ␤-catenin by preventing and shRNA-mediated knockdown. Using gene expression profiling TCF4 loading onto a promoter. This was neither due to direct binding and chromatin immunoprecipitation followed by microarray anal- of WT1 to the TCF binding site nor to interaction between WT1 and TCF4, ysis (ChIP–ChIP) we identified genes bound and regulated by WT1. but by competition of WT1 and TCF4 for CBP. WT1 interference with Wnt WT1 targets included genes of the Wnt pathway, which is required signaling represents an important mode of its action relevant to the for normal renal development (26) and is deregulated in Wilms suppression of tumor growth and guidance of development. tumors (5). WT1 inhibited Wnt function during Xenopus develop- ment and interfered with Wnt-mediated transcription through the ChIP–ChIP ͉ microarray ͉ tumor suppressor CREB binding protein (CBP) cofactor. Collectively these data suggest that one critical role of WT1 in development and tumori- he genetic etiology of Wilms tumorigenesis is heterogeneous genesis is to modulate the Wnt signaling pathway. Tincluding loss-of-imprinting of IGF2 (1), deletions and muta- Results tions of WT1 (reviewed in ref. 2) and the recently identified WTX (3) genes. In addition, somatic mutations in ␤-catenin leading to a Identification of Direct Targets of WT1 by ChIP in Combination with stabilized protein are found in 15% of cases and curiously almost Promoter Microarray Analysis. ChIP–ChIP was initially performed all of these mutation cases are found in patients lacking functional in Wilms tumor-derived CCG99–11 cells, which express low levels WT1 alleles (4–7). of wild-type WT1 protein. The resulting hybridization signals were The WT1 tumor suppressor gene encodes a zinc finger transcrip- low and only 8 promoter regions were identified on all 3 NimbleGen tion factor, possibly yielding up to 32 different isoforms (8). The HG18 RefSeq arrays and 57 promoters by 2/3 arrays (Fig. S1A). major isoforms differ in the presence or absence of amino acids Previously identified direct targets of WT1 such as IFI16 (21) and KTS in the zinc finger region and the presence or absence of a 17-aa MKP3 (13) were not scored by this experiment. To increase the stretch in the middle of the protein. The ϪKTS isoforms have been sensitivity of the ChIP–ChIP assay we used CCG-5.1 cells engi- linked to DNA binding-mediated transcriptional control whereas neered to stably express additional WT1-A in an inducible manner the ϩKTS isoforms have been implicated in RNA processing as well (Fig. S1B). In contrast to the apoptotic phenotype we (27) and (9). Renal agenesis in the Wt1 knockout mouse and the presence of others (16) observed upon WT1 induction in Saos2 osteosarcoma cells, further induction of WT1 in CCG-5.1 did not yield apoptosis constitutional mutations in WT1 in a number of renal developmen- or cell cycle arrest. ChIP–ChIP analysis of CCG-5.1 cells identified tal syndromes indicate a critical role for WT1 in kidney develop- 643 promoters found by 3/3 arrays and 2415 promoters found in 2/3 ment. WT1 is also involved in the development of other organs arrays (Fig. 1A). Hence the higher signal generated by WT1 including spleen, heart, and liver (10–12). In cell culture systems WT1 generally acts as a growth suppressor (13–18) but its overex- pression in a number of tumor types such as colon and thyroid (19, Author contributions: M.K.-H.K. and J.D.L. designed research; M.K.-H.K. and T.J.M. per- 20) suggests that it may act as an oncogene as well. Accordingly formed research; M.K.-H.K. contributed new reagents/analytic tools; M.K.-H.K., P.O., J.M.F., knockdown of WT1 led to decreased growth of a Wilms tumor cell and A.A.-J.G. analyzed data; and M.K.-H.K. and J.D.L. wrote the paper. line suggesting a permissive role in growth in some cases of Wilms The authors declare no conflict of interest. tumor (21). This article is a PNAS Direct Submission. WT1 activates or represses gene transcription depending on the 1To whom correspondence should be addressed. E-mail: [email protected]. cellular, developmental and promoter context. WT1 targets have This article contains supporting information online at www.pnas.org/cgi/content/full/ been sought to explain its function in development and growth 0901591106/DCSupplemental. 11154–11159 ͉ PNAS ͉ July 7, 2009 ͉ vol. 106 ͉ no. 27 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0901591106 Downloaded by guest on September 28, 2021 A Table 2. Gene ontology of the genes bound and differentially B regulated by WT1 KEGG pathway term Genes MAPK signaling pathway DUSP16, DDIT3, MAPKAPK2, PPP3CB, NLK, RRAS2, JUN, DUSP6, DUSP5 Axon guidance NRP1, PPP3CB, ROBO2, CXCR4, ITGB1, GNAI3, EFNA1 C Wnt signaling CCND2, LEF1, BTRC, PPP3CB, NLK, JUN, DKK2, TBL1X, DACT1* *Not recognized in DAVID functional annotation system and manually added. the SP1, MAZ, and ZNF219 transcription factors. The MatInspec- tor tool (33) revealed 340 overlapping WT1/SP1 sites, 186 over- Fig. 1. Identification of WT1-bound promoter regions and motif analysis. (A) lapping WT1/EGR1 sites and 149 sites where all three factors may Genes identified by ChIP–ChIP at WT1-induced level in CCG-5.1 are shown in Venn diagrams. (B) A total of 199 bound and differentially regulated genes by WT1 compete for binding (examples shown in Fig. S2). There were a total (shown in bold) were identified in the comparison from the LOF (by shRNA) and of 675 overlapping sites spread over 437 of the 643 promoters. This GOF (CCG-5.1) expression array sets and ChIP–ChIP. (C) The representative motif information suggests that WT1 target genes may have a complex for each cluster was generated using the STAMP platform. The SOMBRERO motifs mode of regulation that depends on the presence and/or activity of were created by clustering the original redundant set of 68 motifs produced by WT1, and other transcription factors. Furthermore, among previ- the algorithm. ously identified in vitro WT1 motifs, EGR1 site was more common than others such as WRE and WTE sites (Table S1). overexpression identified many more putative WT1 targets but Gene Expression Profiles in Gain-of-Function and Loss-of-Function could obscure occasionally, because the enhanced noise caused by Systems. To identify genes differentially regulated by WT1, we WT1 induction led the peak detection program to miss several performed microarray analysis in both gain-of-function (GOF) peaks in this analysis (Fig. S1C). However, some peaks identified in (Fig. S1B) and loss-of-function (LOF) (21) systems. In the initial CCG99–11 were absent without any increase in baseline hybrid- screen for bound and regulated genes, we applied a low stringency ization to other probe sets of the promoter. This could represent cut-off (P Ͻ 0.005, Ն1.5-fold change). Microarray profiling showed redistribution of WT1 among genomic sites upon high-level ex- that 455 genes were regulated in the biological triplicates.
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