Epigenetic Histone Modifications in Cell differentiation and Cancer
Gene regulation is an important molecular mechanism underlying cell growth, proliferation, differentiation, and death during normal development and life cycles. Abnormality in gene expression such as epigenetic silencing of tumor suppressor genes can have harmful consequences leading to cell over-proliferation and tumorigenesis. In eukaryotic cells, chromatin is composed of histone proteins and DNA molecules and is the physiological template upon which gene regulation occurs. A flurry of recent literature demonstrates that covalent histone modifications contribute greatly to epigenetic form of gene regulation.
My long-term research interest is to study how histone modifications regulate gene expression during normal development and under disease conditions. Currently, I investigate the role of histone citrullination catalyzed by peptidylarginine deiminase 4 (PAD4) in transcriptional repression of tumor suppressor genes, as well as a unique role of histone hyper-citrullination in antibacterial innate immunity mediated by a highly decondensed chromatin structure termed neutrophil extracellular traps (NETs). In a 2004 Science paper, I showed that PAD4 regulates histone Arg methylation by converting mono-methyl-Arg to citrulline via a novel demethylimination reaction in addition to its well-established activity to convert protein Arg residues to citrulline. PAD4 is a fascinating molecule to study not only because of its dual enzymatic activities in catalyzing deimination of Arg and demethylimination of methyl-Arg but also because of its health relevance to human diseases including cancers and rheumatoid arthritis. Studies from my group over the last several years have contributed significantly to our current knowledge of the physiological function of PAD4 as well as the involvement of PAD4 over-expression in the etiology of cancers and rheumatoid arthritis. We are poised to make novel discoveries in several research areas (see below) and contribute to the field of chromatin structure and function.
(1) Histone modifications in p53-target gene expression
(2) Design and evaluate the therapeutic potential of PAD4 inhibitors
(3) Histone hyper-citrullination in higher order chromatin structure and innate immunity
(4) OKL38 and its cooperation with p53 in regulating mitochondria structure and function
Figure 1. Epigenetic histone modifications at multiple of histone sites regulate chromatin function, such as transcription of tumor suppressor genes and chromatin folding/unfolding, which are two research directions pursued in my laboratory.
Figure 2. Our current research is focused on understanding basic cell biological and developmental processes, such as stem cell pluripotency, cell differentiation and dedifferenation, as well as cell cycle and death. By understanding the epigenetic mechanisms underlying these normal processes, we hope to generate new tools prevent and control human diseases, such as cancer and autoimmune diseases.