The overarching goal of the three aims proposed for this project is to define genetic/epigenetic mechanisms that regulate the fine balance between human health and disease. My group identified CHD5 as a tumor suppressor mapping to 1p36-a region of the genome frequently deleted in human cancer. We defined Chd5 as a dosage-sensitive regulator of chromatin dynamics, and most recently, implicate Chd5 deficiency in male infertility and autism. The studies described in this proposal will build upon these discoveries by establishing novel models of human disease, assessing disease phenotypes, determining the mechanism(s) whereby Chd5 regulates chromatin to transcriptionally modulate disease pathways in normal cells, and elucidating how altered dosage of Chd5 affects chromatin dynamics in diseases such as cancer, infertility, and autism. The goal of Aim 1 is to generate mouse models with enhanced and compromised dosage of Chd5. This will be done using chromosome engineering, a genomic approach we used previously to establish mouse models with copy number variations found in cancer and autism. The goal of Aim 2 is to analyze existing Chd5 mouse models as well as the novel ones we generate in Aim 1 for phenotypes of cancer, infertility, and autism. This will be done using the quantitative in vivo functional assays we developed and used to define Chd5 as a suppressor of sarcoma development, as being vital for reproductive fitness, and as being essential in the brain. The goal of Aim 3 is to define the mechanism(s) whereby Chd5- mediated chromatin dynamics affects nuclear structure and regulates expression of disease pathways on a genome-wide scale. This will be accomplished by using microscopy to visualize H2B-eGFP patterns and by using RNA-seq, ChIP-seq, and bioinformatics to characterize global gene expression signatures, Chd5-bound loci, and covalent histone modifications in fibroblasts, spermatids, and neurons obtained from mice with altered dosage of Chd5. This project will establish unique models for several prevalent human diseases, will define the role of altered Chd5 dosage in disease phenotypes, and will provide new insights into the biological role of Chd5-mediated chromatin dynamics in health and disease. In addition, this work will elucidate epigenetic processes essential for preventing cancer, for ensuring fertility, and for normal brain function, presenting an unprecedented opportunity to identify convergence between cancer, infertility, and autism that may impact how these diseases are treated in the future.

Public Health Relevance

This project seeks to elucidate the role of CHD5 in controlling chromatin events that regulate human health and disease. We discovered that this protein plays a role in cancer, infertility and autism and we will now determine the mechanism(s) involved. This work has the potential to be broadly applicable, as it will ultimately provide a strong geneti foundation for the design of more effective therapeutic strategies for cancer, infertility, and autism.

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
Exploratory/Developmental Grants (R21)
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Genetics of Health and Disease Study Section (GHD)
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Mirochnitchenko, Oleg
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Cold Spring Harbor Laboratory
Cold Spring Harbor
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Li, Wangzhi; Mills, Alea A (2014) Architects of the genome: CHD dysfunction in cancer, developmental disorders and neurological syndromes. Epigenomics 6:381-95
Li, Wangzhi; Mills, Alea A (2014) Packing for the journey: CHD5 remodels the genome. Cell Cycle 13:1833-4
Li, Wangzhi; Wu, Jie; Kim, Sang-Yong et al. (2014) Chd5 orchestrates chromatin remodelling during sperm development. Nat Commun 5:3812