Doctoral Dissertations

Date of Award

12-2011

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Biochemistry and Cellular and Molecular Biology

Major Professor

Bruce McKee

Committee Members

Sundaresan Venkatachalam, Mariano Labrador, Ranjan Ganguly, Seung Baek

Abstract

Murine model organisms are an essential tool in the scientific community quest to decipher the molecular etiology of human diseases. Currently, several methods are used to induce or reproduce human diseases in mouse models using advanced genetic engineering techniques to mutate the wild-type genes. We utilized the Baygenomics gene-trap method to study the effects of two mammalian genes: FOXN3 and CHD2. The Forkhead Box (FOX) family of transcription factors shares a common DNA-binding domain and has been associated with organ development, differentiation, cell growth and proliferation, and cancer. Meanwhile, the CHD (Chromodomain helicase DNA binding protein) family of proteins is known to be involved in chromatin remodeling and regulation of gene expression. Phenotypic analysis of Foxn3 mutant animals revealed its indispensible role in craniofacial and embryonic development, embryonic lethality, expression of bone morphogenetic proteins, and spontaneous development of cancers in heterozygous and homozygous mutant mice. Preliminary evaluation of molecular mechanisms of FOXN3 signifies deregulation of cell-cycle checkpoint proteins Cyclin-B1 and CDK2 as the underlying etiology of tumors. Chd2 mutant mice exhibit spontaneous thymic and splenic lymphomas and reduced lifespan which can be restored through Chd2 re-expression in the thymus. At the molecular level, CHD2 deficiency reduces Puma (p53-upregulated modulator of apoptosis) induction after DNA damage in mouse thymocytes and HCT116 cells. Additionally, CHD2 is enriched at the Puma locus after DNA damage. CHD2-deficient cells also exhibit global reduction of active transcription markers H3K9-Acetylated and H4K8-Acetylated.

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