Medical Genetics clinical staff profiles

Stephen J. Tapscott, M.D., Ph.D.

Full Member of Fred Hutchinson Cancer Research Center
Professor of Neurology
Adjunct Professor of Pathology

FHCRC, Box 358080
1124 Columbia Street, C3-168
Seattle, WA 98104-2092
Phone: 206-667-4499, 206-667-4286
FAX: 206-667-6524
E-mail: stapscot@fhcrc.org

Research Profile (Community of Science)

Research Program:

Chromatin Structure and the Regulation of Gene Transcription: Skeletal myogenesis is regulated by a family of related basic Helix-loop-Helix (bHLH) proteins: MyoD, Myf5, myogenin, and MRF4. MyoD and Myf5 are necessary to specify the skeletal muscle lineage, whereas myogenin is necessary for terminal differentiation. The expression of MyoD is sufficient to convert a fibroblast to a skeletal muscle cell. We have been using this as a model to study how a single initiating event, in this case the expression of the MyoD transcription factor, can orchestrate a highly complex and predictable response. We have shown that MyoD can be recruited to specific loci through interaction with resident homeodomain proteins and inititiate chromatin remodeling at these loci prior to stable DNA binding. Through mechanisms such as this, MyoD directly regulates genes expressed throughout the myogenic program and achieves promoter-specific regulation of its own binding and activity through a feed forward mechanism. These studies are beginning to show how master regulatory factors drive programs of cell differentiation.

Neurogenic bHLH proteins: Similar to myogenesis, neurogenesis is regulated by a family of bHLH proteins related to NeuroD. We have been able to demonstrate that non-neuronal cells can be converted into neurons by the forced expression of neuroD family members. Different family members have varying abilities to activate neural promoters and to induce neurogenesis. Therefore these genes are good candidates for establishing and maintaining specific neuronal identities in subpopulations of neurons. We are now studying the molecular characteristics that confer specific activities on family members. We have also disrupted one of the neuroD family members, neuroD2, in mice and have demonstrated its role in the differentiation and survival of distinct neuronal populations.

Myotonic Dystrophy: Myotonic dystrophy is a dominantly inherited disease characterized by a myotonic myopathy, cardiac conduction defects, and cataracts. In a majority of families it is caused by the expansion of a CTG repeat in the 5-prime non-coding region of a protein kinase gene, the dystrophia myotonia protein kinase (DMPK) gene on chromosome 19q13.3, the DM1 locus. We have shown that the expansion of the repeat alters the local chromatin structure and results in decreased expression of a neighboring gene, the SIX5 gene. SIX5 is a member of a family of homeobox proteins thought to be important in skeletal muscle development and for expression of a subunit of the sodium pump. To determine if decreased expression of SIX5 contributes to the phenotype of myotonic dystrophy, we disrupted the gene in mice. Mice deficient for SIX5 developed cataracts, one of the major features of human myotonic dystrophy. We are currently studying the normal role of the CTG repeats at the DM1 locus and have shown that they are an integral component of a CTCF dependent insulator element positioned between the DMPK promoter and the enhancer for the SIX5 gene. Ongoing work is focused on the function of the insulator element and the role of the CTG repeat in chromatin structure.

Therapeutic Approaches to Duchenne Muscular Dystrophy: Duchenne muscular dystrophy is caused by a mutation in the dystrophin gene on the X-chromosome, resulting in a severe muscle disease. Studies in mice suggest that dystrophin can be delivered to skeletal muscle either by viral vectors, such as adeno-associated virus (AAV), or by delivery of muscle stem cells. We are interested in determining whether bone marrow derived stem cells or skeletal muscle derived stem cells can be developed as a possible source of skeletal muscle for the treatment of Duchenne's muscular dystrophy. In addition, we are collaborating with Jeff Chamberlain at the University of Washington to test pre-clinical models of AAV delivery of dystrophin to skeletal muscle.

DNA Palindromes as a Platform for Gene Amplification in Human Cancers: In collaboration with Meng-Chao Yao at the FHCRC, we have shown that the formation of a large DNA palindrome is the initial and rate limiting step in gene amplification in a model system of DHFR amplification in CHO cells. We have also shown that DNA palindrome formation is widespread in human cancers and associated with regions of gene amplification. We are now determing the mechanisms of initial palindrome formation, their role in cancer cell biology, and their utility for cancer detection and therapy.

Investigator: Dr. Tapscott is an Assistant Member, Divisions of Clinical Research and Molecular Medicine, Full Member Fred Hutchinson Cancer Research Center, Adjunct Professor of Pathology, and Professor, Department of Medicine, Division of Neurology, University of Washington

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