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
DUX4-induced dsRNA and MYC mRNA stabilization activate apoptotic pathways in human cell models of facioscapulohumeral dystrophy.. PLoS genetics. 13(3):e1006658.. 2017.
Mutations in DNMT3B Modify Epigenetic Repression of the D4Z4 Repeat and the Penetrance of Facioscapulohumeral Dystrophy.. American journal of human genetics. 98(5):1020-9.. 2016.
Distinct Activities of Myf5 and MyoD Indicate Separate Roles in Skeletal Muscle Lineage Specification and Differentiation.. Developmental cell. 36(4):375-85.. 2016.
Clinical trial preparedness in facioscapulohumeral muscular dystrophy: Clinical, tissue, and imaging outcome measures 29-30 May 2015, Rochester, New York.. Neuromuscular disorders : NMD. 26(2):181-186.. 2016.
Model systems of DUX4 expression recapitulate the transcriptional profile of FSHD cells.. Human molecular genetics.. 2016.
Conversion of MyoD to a Neurogenic Factor: Binding Site Specificity Determines Lineage.. Cell reports. 10(12):1937-46.. 2015.
Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2.. European journal of human genetics : EJHG.. 2015.
Genetic and epigenetic contributors to FSHD.. Current opinion in genetics & development. 33:56-61.. 2015.
Immunohistochemical Characterization of Facioscapulohumeral Muscular Dystrophy Muscle Biopsies.. Journal of neuromuscular diseases. 2(3):291-299.. 2015.
DUX4-induced gene expression is the major molecular signature in FSHD skeletal muscle.. Human molecular genetics.. 2014.
Facioscapulohumeral dystrophy: the path to consensus on pathophysiology.. Skeletal muscle. 4:12.. 2014.
Multiplex Screen of Serum Biomarkers in Facioscapulohumeral Muscular Dystrophy.. Journal of neuromuscular diseases. 1(2):181-190.. 2014.
The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1.. American journal of human genetics. 93(4):744-51.. 2013.
Discriminative motif analysis of high-throughput dataset.. Bioinformatics (Oxford, England).. 2013.
MyoD Is a Tumor Suppressor Gene in Medulloblastoma.. Cancer research. 73(22):6828-37.. 2013.
DUX4 binding to retroelements creates promoters that are active in FSHD muscle and testis.. PLoS genetics. 9(11):e1003947.. 2013.
Expanding donor muscle-derived cells for transplantation.. Current protocols in stem cell biology. Chapter 2:Unit2C.4.. 2013.
Myod and H19-Igf2 locus interactions are required for diaphragm formation in the mouse.. Development (Cambridge, England). 140(6):1231-9.. 2013.