Stephen J. Tapscott
M.D., University of Pennsylvania, Medicine, 1982.
Ph.D., University of Pennsylvania, 1982.
B.A., Hampshire College, 1975.
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.
Microsatellite and Macrosatellite Diseases:
We are studying the transcription and epigenteic modifications at triplet repeat disease loci, particularly DM1 and FMR1, as well as the D4Z4 macrosatellite repeat at the FSHD locus. We have identified bidirectional transcription and the generation of small RNAs at both the micro- and macrosatellite repeat regions, indicating that these repetitive regions might induce local heterochromatin structures.
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 Methylation and DNA Palindromes 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 associated with regions of gene amplification inhuman cancers. We are now determing the mechanisms of initial palindrome formation, their role in cancer cell biology, and their utility for cancer detection and therapy. In addition, we have developed a genome-wide assay for determining differential DNA methylation. Using this assay, we have detected methylated loci associated with medulloblastoma and rhabdomyosarcoma pediatric malignancies.
Board Certified neurologist with special expertise in neurogenetics and neuromuscular disease
American Academy of Neurology
American Association for the Advancement of Science
American Neurological Association
Fundamental differences in promoter CpG island DNA hypermethylation between human cancer and genetically engineered mouse models of cancer.. Epigenetics : official journal of the DNA Methylation Society. 8(12):1254-60.. 2013.
Intrinsic epigenetic regulation of the D4Z4 macrosatellite repeat in a transgenic mouse model for FSHD.. PLoS genetics. 9(4):e1003415.. 2013.
Comparison of endogenous and overexpressed MyoD shows enhanced binding of physiologically bound sites.. Skeletal muscle. 3(1):8.. 2013.
Mapping contrast agent uptake and retention in MRI studies of myocardial perfusion: case control study of dogs with Duchenne muscular dystrophy.. The international journal of cardiovascular imaging.. 2012.
Facioscapulohumeral muscular dystrophy: consequences of chromatin relaxation.. Current opinion in neurology. 25(5):614-20.. 2012.
Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.. Nature genetics. 44(12):1370-4.. 2012.
Correlation analysis of clinical parameters with epigenetic modifications in the DUX4 promoter in FSHD.. Epigenetics : official journal of the DNA Methylation Society. 7(6):579-584.. 2012.
DUX4 Activates Germline Genes, Retroelements, and Immune Mediators: Implications for Facioscapulohumeral Dystrophy.. Developmental cell. 22(1):38-51.. 2012.
Assessment of palindromes as platforms for DNA amplification in breast cancer.. Genome research. 22(2):232-45.. 2012.
Epigenetic regulation of the X-chromosomal macrosatellite repeat encoding for the cancer/testis gene CT47.. European journal of human genetics : EJHG. 20(2):185-191.. 2012.
Generation of Isogenic D4Z4 Contracted and Noncontracted Immortal Muscle Cell Clones from a Mosaic Patient: A Cellular Model for FSHD.. The American journal of pathology.. 2012.
Activation of Notch Signaling During ex vivo Expansion Maintains Donor Muscle Cell Engraftment.. Stem cells (Dayton, Ohio).. 2012.
Genetic and epigenetic determinants of neurogenesis and myogenesis.. Developmental cell. 22(4):721-35.. 2012.
Genome-wide DNA methylation studies suggest distinct DNA methylation patterns in pediatric embryonal and alveolar rhabdomyosarcomas.. Epigenetics : official journal of the DNA Methylation Society. 7(4). 2012.
Analyzing Cellular Immunity to AAV in a Canine Model Using ELISPOT Assay.. Methods in molecular biology (Clifton, N.J.). 792:65-74.. 2012.
Polycomb-mediated repression during terminal differentiation: what don't you want to be when you grow up? Genes & development. 25(10):997-1003.. 2011.
Facioscapulohumeral muscular dystrophy and DUX4: breaking the silence.. Trends in molecular medicine. 17(5):252-8.. 2011.
MyoD directly up-regulates premyogenic mesoderm factors during induction of skeletal myogenesis in stem cells.. The Journal of biological chemistry. 286(4):2517-25.. 2011.
Differential genomic targeting of the transcription factor TAL1 in alternate haematopoietic lineages.. The EMBO journal. 30(3):494-509.. 2011.
Genome-wide transcription factor binding: beyond direct target regulation.. Trends in genetics : TIG. 27(4):141-8.. 2011.
Immunodetection of human double homeobox 4.. Hybridoma (2005). 30(2):125-30.. 2011.
Immune Responses to rAAV6: The Influence of Canine Parvovirus Vaccination and Neonatal Administration of Viral Vector.. Frontiers in microbiology. 2:220.. 2011.