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Investigation of the Molecular Function of CHD7, the Protein Implicated in CHARGE Syndrome, Using Next-Generation Genomics

Schnetz, Michael Paul
http://rave.ohiolink.edu/etdc/view?acc_num=case1275581022

Abstract Details

2010, Doctor of Philosophy, Case Western Reserve University, Genetics.
Eukaryotes use chromatin to package large, complex genomes into the nucleus of their cells. As such, chromatin structure plays a key role in virtually all DNA-centric processes including gene transcription. Specifically, chromatin packaging and specific histone chemical modifications function to regulate gene expression. The chromodomain helicase DNA-binding (CHD) protein family is a class of chromatin remodeling enzymes that play roles in these processes. Despite what is known about the CHD protein family, the molecular function of CHD7 has not been characterized. CHD7 is required for proper mammalian development as mutations in CHD7 result in a developmental disease known as CHARGE syndrome in which multiple organ systems are affected including the eyes, heart, and genitals. Using a genomics approach, the molecular function of CHD7 was investigated. CHD7 was found to bind chromatin largely outside of gene transcriptional start sites in an overall pattern that was cell-specific. CHD7 binding correlates with cell-specific gene expression and harbors features of gene enhancer elements, namely H3K4me1 and DNaseI hypersensitivity. CHD7, to a less extent, is found also at gene promoters marked with H3K4me3. CHD7 binds H3K4me via its chromodomains. In mouse ES cells, CHD7 binding tracks with H3K4me1 methylation during cellular differentiation and colocalizes with ES-specific transcription factors including Oct4, Nanog, and Sox2. CHD7 binding sites represent functional enhancers as tested in luciferase reporter assays. Finally, loss of CHD7 results in both expression increases as well as decreases, however, CHD7 binding correlates with increased gene expression. Collectively, these studies indicate that CHD7 functions to regulate cell-specific gene transcription through enhancer interactions by limiting the expression of its target genes. The function of CHD7 uncovers a novel regulatory mechanism at gene enhancers that suggests the overall regulatory output of any enhancer is the combination of both positive and negative-acting factors.
Peter Scacheri, C (Advisor)
232 p.
Genetics
CHD7; CHARGE Syndrome; Chromatin Remodeling; mouse ES cells

Recommended Citations

Citations

  • Schnetz, M. P. (2010). Investigation of the Molecular Function of CHD7, the Protein Implicated in CHARGE Syndrome, Using Next-Generation Genomics [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1275581022

    APA Style (7th edition)

  • Schnetz, Michael. Investigation of the Molecular Function of CHD7, the Protein Implicated in CHARGE Syndrome, Using Next-Generation Genomics. 2010. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1275581022.

    MLA Style (8th edition)

  • Schnetz, Michael. "Investigation of the Molecular Function of CHD7, the Protein Implicated in CHARGE Syndrome, Using Next-Generation Genomics." Doctoral dissertation, Case Western Reserve University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1275581022

    Chicago Manual of Style (17th edition)

case1275581022
338
© 2010, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.