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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD056369-05
Application #
8100186
Study Section
Special Emphasis Panel (ZRG1-GTIE-A (01))
Program Officer
Oster-Granite, Mary Lou
Project Start
2007-09-20
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$305,786
Indirect Cost
Name
Case Western Reserve University
Department
Genetics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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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Factor, Daniel C; Corradin, Olivia; Zentner, Gabriel E et al. (2014) Epigenomic comparison reveals activation of ""seed"" enhancers during transition from naive to primed pluripotency. Cell Stem Cell 14:854-63
Balow, Stephanie A; Pierce, Lain X; Zentner, Gabriel E et al. (2013) Knockdown of fbxl10/kdm2bb rescues chd7 morphant phenotype in a zebrafish model of CHARGE syndrome. Dev Biol 382:57-69
Akhtar-Zaidi, Batool; Cowper-Sal-lari, Richard; Corradin, Olivia et al. (2012) Epigenomic enhancer profiling defines a signature of colon cancer. Science 336:736-9
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Tian, Cong; Yu, Heping; Yang, Bin et al. (2012) Otitis media in a new mouse model for CHARGE syndrome with a deletion in the Chd7 gene. PLoS One 7:e34944
Goodnough, L Henry; Chang, Andrew T; Treloar, Charles et al. (2012) Twist1 mediates repression of chondrogenesis by ?-catenin to promote cranial bone progenitor specification. Development 139:4428-38
Zentner, Gabriel E; Scacheri, Peter C (2012) The chromatin fingerprint of gene enhancer elements. J Biol Chem 287:30888-96
Zentner, Gabriel E; Saiakhova, Alina; Manaenkov, Pavel et al. (2011) Integrative genomic analysis of human ribosomal DNA. Nucleic Acids Res 39:4949-60

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