All ETDs from UAB

Advisory Committee Chair

Hao Jiang

Advisory Committee Members

Tim Townes

Ravi Bhatia

Gwendalyn D King

Xinyang Zhao

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

It is unclear how H3K4 methylation, an epigenetic modification associated with gene activation, regulates stem cell fate determination and tumorigenesis. DPY30 is one of the core subunits of the SET1/MLL complex in mammals responsible for H3K4me. DPY30 enhances the H3K4me activity of the SET1/MLL complex. Here, I sought to define role of DPY30 and H3K4me3 in postnatal neurogenesis and hematopoietic malignancies. Using a conditional knockout model, I found that Dpy30 deficiency halts the development of postnatal hippocampus, the subventricular zone, and cerebellum. Deficiency in cerebellum is most likely the cause of uncoordinated ataxia-like movements in these mice. By deleting Dpy30 in neurogenic regions of the brain, I demonstrated that efficient H3K4 tri-methylation is required for self-renewal and differentiation of neural stem cells (NSCs) into both neural and glial lineages in a cell-intrinsic manner. Dpy30 binds to, and directly regulates H3K4 tri-methylation at transcription start sites (TSS) of several genes important for neurogenesis. Dpy30 depletion inhibits efficient induction of these genes. These findings link a critical epigenetic mark for active gene expression to normal functioning of NSCs and may have implications in neurodevelopmental disorders. Binding of MYC to its genomic loci has been corelated with several “activating” epigenetic histone modifications. Here, I showed that core subunits of the SET1/MLL complex, including DPY30, were frequently amplified in human cancers. I thus, chose Burkitt’s lymphoma, a MYC-driven cancer to investigate the relationship between H3K4me3 and MYC in MYC-driven malignancies. I showed that DPY30 promoted expression of endogenous MYC, and also facilitated binding of MYC to its genomic targets by regulating chromatin accessibility. Parallel study in the lab also showed that Dpy30 heterozygosity did not affect animal physiology and life span. This suggested that while the full level of Dpy30 was dispensable for normal cells, and that cancer cells were highly dependent on higher levels of Dpy30. This created a therapeutic window allowed me to pharmacologically target DPY30 as an “epigenetic target.” To target DPY30’s activity, we generated cell-penetrating peptides that corresponded to C-terminus tail of ASH2L, DPY30’s binding partner in the SET1/MLL complex. These peptides inhibit binding of DPY30 to ASH2L and suppress the growth of MLL-rearranged leukemia and Burkitt’s lymphoma cells.

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