title: Fgfr3 is a transcriptional target of Ap2delta and Ash2l-containing histone methyltransferase complexes.
abstract: Polycomb (PcG) and trithorax (trxG) proteins play important roles in establishing lineage-specific genetic programs through induction of chromatin modifications that lead to gene silencing or activation. Previously, we described an association between the MLL/SET1 complexes and a highly restricted, gene-specific DNA-binding protein Ap2delta that is required for recruitment of the MLL/SET1 complex to target Hoxc8 specifically. Here, we reduced levels of Ap2delta and Ash2l in the neuroblastoma cell line, Neuro2A, and analyzed their gene expression profiles using whole-genome mouse cDNA microarrays. This analysis yielded 42 genes that are potentially co-regulated by Ap2delta and Ash2l, and we have identified evolutionarily conserved Ap2-binding sites in 20 of them. To determine whether some of these were direct targets of the Ap2delta-Ash2l complex, we analyzed several promoters for the presence of Ap2delta and Ash2l by chromatin immunoprecipitation (ChIP). Among the targets we screened, we identified Fgfr3 as a direct transcriptional target of the Ap2delta-Ash2l complex. Additionally, we found that Ap2delta is necessary for the recruitment of Ash2l-containing complexes to this promoter and that this recruitment leads to trimethylation of lysine 4 of histone H3 (H3K4me3). Thus, we have identified several candidate targets of complexes containing Ap2delta and Ash2l that can be used to further elucidate their roles during development and showed that Fgfr3 is a novel direct target of these complexes.
authors.affiliation: Department of Biological Chemistry, University of California Los Angeles School of Medicine, Los Angeles, California, USA.
authors.forename: Cheryl C
authors.initials: CC
authors.lastname: Tan
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Walsh
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019143:Evolution, Molecular; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D056426:Genetic Loci / Q000235:genetics; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D008745:Methylation; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics* / Q000378:metabolism; D050656:Transcription Factor AP-2 / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C120115:Ash2l protein, mouse; D004268:DNA-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; C493671:Tfap2d protein, mouse; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C496366:Fgfr3 protein, mouse; D051498:Receptor, Fibroblast Growth Factor, Type 3