CHARGE syndrome is a congenital disease characterized by malformations of multiple organs. ~70% of CHARGE syndrome cases are caused by loss-of-function de novo mutations in the CHD7 gene (coding for chromodomain helicase DMA-binding protein 7). Little information is available about the normal function of the CHD7 protein and its role in human development and disease. Our preliminary studies demonstrate that CHD7 is a nuclear protein that directly binds to multiple genes, including HOX genes (HOXA5, HOXA10, and HOXA11) and imprinted genes (IGF2 and H19) that are essential for normal embryonic development. The proposed research tests the hypothesis that the malformations seen in patients with CHARGE syndrome are caused by aberrant transcription of specific CHD7 target genes. This hypothesis will be tested in 3 Specific Aims.
In Aim 1, we will evaluate a subset of the CHD7 target genes to determine if CHD7 directly regulates their expression. Specifically, expression of 50 CHD7 targets will quantified in cell culture before and after knockdown of CHD7 by RNAi. In addition, to determine if anomalies in CHARGE syndrome are due to dysregulated expression of HOX, Igf2, and H19, we will analyze expression of these genes in developing Chd7 mutant mice that are an excellent model CHARGE syndrome.
In Aim 2, we will investigate the mechanism by which CHD7 is recruited to its target genes, using in vitro and in vivo assays designed to reveal interactions between CHD7 and various histone modifications on chromatin.
In Aim 3, we will identify CHD7 targets that directly depend on CHD7 during early development, using an unbiased genomics approach that combines the technique of chromatin immunoprecipitation on microarrays (ChlP-chip) with expression profiling of wild type and mutant mouse ES cells. By identifying and characterizing the genes that are directly regulated by CHD7, we expect to learn more about (1) normal human development, (2) the causes of the isolated birth defects that make up the spectrum of anomalies in CHARGE, and (3) the etiology of this rare syndrome. In addition to furthering our understanding of the clinical implications of genes regulated by CHD7, we anticipate gaining a significant amount of knowledge about the molecular mechanisms of transcriptional regulation by delineating the interactions between CHD7 and its target genes.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Special Emphasis Panel (ZRG1-GTIE-A (01))
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Oster-Granite, Mary Lou
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Case Western Reserve University
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Zentner, Gabriel E; Balow, Stephanie A; Scacheri, Peter C (2014) Genomic characterization of the mouse ribosomal DNA locus. G3 (Bethesda) 4:243-54
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