|Xinyang Zhao, Ph.D.
Assistant Professor, Department of Biochemistry & Molecular Genetics
Areas of Focus: The mechanisms of transcriptional and epigenetic regulations using hematopoiesis as a model system
My research interest is to study the mechanisms of transcriptional and epigenetic regulations using hematopoiesis as a model system. Hematopoiesis is a tightly programmed epigenetic process through interplay between extracellular signaling and transcriptional regulation. Abnormal hematopoiesis i.e. leukemogenesis is caused by mutation or translocations of tyrosine kinases or transcription factors, which result in blockage of terminal differentiation and unchecked proliferation. As the hematopoietic stem cell (HSC) is differentiated into different lineage cells, chromatin structures of lineage specific genes are altered accordingly through the recruitment of chromatin remodeling proteins by transcription factors. Among different histone modifications, histone is arginine methylated. Arginine methyl transferases (PRMT1, PRMT4 and 5) are crucial in normal hematopoiesis and leukemogenesis. Not only histone but also transcription factor (RUNX1) critical for hematopoiesis is methylated by arginine methyl transferases (Gene and Development 2008). RUNX1, which is not methylated in hematopoietic stem cell, is methylated by PRMT1 and becomes a transcriptional activator when the HSC is differentiated into myeloid lineage.
My lab will continue to focus on arginine methyl transferases, in particular PRMT5, for their roles in hematopoiesis using cutting edge biochemical approaches as well as genetic approaches. We would like to address the following questions:
- How arginine methyltransferases regulate hematopoietic stem cell self-renewal and differentiation via modulating protein-protein interaction of their substrates? In particular, we will focus on how arginine methylation of RUNX1 impacts on its organization of transcriptional regulatory complex and its ability to coupling transcription to RNA export in blood cells.
- How the enzymatic activities of PRMTs are regulated during hematopoiesis? By purifying novel PRMT complexes from blood cell lines, we will investigate whether PRMTs per se are post-translationally modified in response to extracellular cytokine signals. Modification specific antibodies to PRMTs will be raised to determine how the modified PRMTs regulate the epigenetic status of hematopoietic cells. For example, we found PRMT5 enzymatic activity is dampened when it is phosphorylated by mutant Jak2V617F kinase (Cancer Cell 2011).
- In collaboration with chemistry labs, we are trying to screen small molecule inhibitors for PRMTs with our blood cell based assays. Later we will use mouse leukemia models to test these drug candidates. With the knowledge we learned from leukemia study, we will also expand our research to solid tumors where PRMTs also play important roles.