Graduate Training in Neuroscience
University of Washington
Full Member, Fred Hutchinson Cancer Research Center; Professor, Department of Neurology; Research Affiliate, Center on Human Development & Disability; Adjunct Professor, Department of Pathology
Myotonic dystrophy is caused by the expansion of a CTG repeat in the 5-prime non-translated region of a protein kinase gene, the dystrophia myotonia protein kinase (DMPK) gene. Our lab has shown that the expansion of the repeat alters the local chromatin structure, making it less accessible to nuclear factors and eliminating a hypersensitive site that is adjacent to the triplet repeat. We propose that the regulation of genes in the region of the expanded repeat is impaired as a result of the altered chromatin conformation, making myotonic dystrophy a disease of chromatin structure. We have recently identified an enhancer element in the hypersensitive region adjacent to the normal sized repeat and demonstrated that loss of the hypersensitive site enhancer suppresses expression of the adjacent DMAHP gene. We are currently studying the role of the DMAHP gene in myotonic dystrophy.
Chromatin Structure and the Regulation of Gene Transcription: Initiating gene transcription within native chromatin is a critical aspect of cell differentiation. We are studying the ability of MyoD to remodel chromatin at binding sites in several muscle and non-muscle genes. We have shown that Myod can remodel chromatin and that this activity is dependent of two novel domains of MyoD. We are currently determining the factors that interact with these regions and the mechanism of chromatin remodeling.
The bHLH NeuroD protein is capable of inducingectopic-neurogenesis when expressed in developing frog embryos. We have been studying NeuroD and two new bHLH proteins related to NeuroD, NeuroD2 and NeuroD3. Initial work has led to the recognition that there are at least two related sub-families of neurogenic bHLH genes. One group is expressed early in development and is highly related to the atonal homolog MATH1. This group is expressed in replicating progenitor cells and early neuroblasts, but not at high levels in the mature nervous system.The second group starts to be expressed at the time of neuronal birth and its expression persists in the adult nervous system and is highly related to the neurod gene. Currently, there are three members of this latter group, NeuroD, NeuroD2 andMATH2. These genes are expressed in a partially overlapping fashion and we have shown that NeuroD and NeuroD2 have differential transcriptional activity. Therefore these genes are good candidates for establishing and maintaining specific neuronal identitiesin subpopulations of neurons. We are pursuing homologous recombination to mark and disrupt the expression of NeuroD2 and a related NeuroD3 gene, as well as using in vitro assays to identify direct target genes.