Gene Expression and Regulation Group

Sachiyo Kawamoto, MD, PhD, Principal Investigator

My research program primarily investigates the regulatory mechanisms responsible for the expression of two nonmuscle myosin heavy chain (MHC) genes, MHC-A and MHC-B. Based on previous observations of the distribution and expression of nonmuscle MHC isoforms, we focus on MHC-A gene regulation as it relates to cell type-dependent transcription, including the down-regulation of this gene during muscle cell differentiation. In addition, we are investigating MHC-B gene regulation as it relates to neuron-specific alternative RNA splicing mechanisms. By studying nonmuscle MHC gene regulation, I plan to be involved in two areas of research. The first is muscle differentiation. In spite of substantial progress in our understanding of the mechanisms responsible for muscle-specific gene expression, the manner by which a number of genes, which are active in undifferentiated myoblasts, are inactivated during terminal differentiation of muscle cells has not yet been elucidated. Obviously, the coordinated activation of a subset of genes along with the inactivation of a second subset of genes is required for the myogenic process. The nonmuscle MHC-A gene is an excellent model for studying this down-regulation of gene expression. Indeed, the MHC isoform switch, from nonmuscle MHCs to skeletal muscle MHCs, occurs in the course of muscle differentiation. The second area of research that I am pursuing involves RNA splicing. Although alternative splicing of pre-mRNA is one of the fundamental mechanisms responsible for developmental and cell type-specific regulation of eukaryotic gene expression, the molecular basis for alternative splice site selection in vertebrates is poorly understood. Since nonmuscle MHC-B contains two alternative exons, both of which are only included in neuronal cells, but are regulated differently during development, it provides a good model for studying neuron-specific alternative splicing of pre-mRNA. We are also interested in studying how neuronal cell differentiation and the brain development program coordinate splicing regulatory pathways.