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    Dennis Jacob Bua.
    The physiological state of the genome is chromatin. Chromatin is a dynamic polymer composed of genomic DNA, histone proteins, and other factors. Dysregulation of chromatin homeostasis can lead to diverse human pathologies including cancer. This work focuses on chromatin-based mechanisms of gene regulation; more specifically the (1) targeting and (2) stabilization of gene-regulatory proteins on the chromatin template. In regard to chromatin targeting, not much is known about how gene-regulatory proteins selectively associate with their targets. Herein we detail the discovery of a new targeting factor, the nuclear phospholipid phosphatidylinositol-5-phosphate (PtdIns(5)P). PtdIns(5)P directly interacts with the tumor suppressor ING2 (inhibitor of growth family member 2) in the nucleus to coordinate gene expression of select ING2 targets. In regard to chromatin stabilization, lysine methylation is a principle mechanism for retaining chromatin-effector modules at discrete chromatin zones. Numerous lysine methylation events have been discovered on the major protein component of chromatin, histones, but relatively few specific modules have been characterized to sense these modifications. We screened through a library of putative methyl-lysine binding domains, which resulted in the identification of three novel chromatin binding modules. Taken together these data shed insight into the molecular modes of action of gene regulation by chromatin and phosphoinositide pathways.
    Digital Access   2012