Department of Cell and Developmental Biology / Wellstone Program

Academic Background

2013-Present
Associate Professor - University of Massachusetts Medical School
Research: Epigenetics; Muscle development and disease, FSHD; Rett Syndrome

2011-Present
Affiliate Investigator - Sen. Paul D. Wellstone Cooperative Research Center for FSHD

2010-2013
Principal Scientist - Boston Biomedical Research Institute

2001-2010
Assistant Professor - Department of Cell and Developmental Biology - University of Illinois at Urbana-Champaign

1997-2001
Postdoctoral fellow - Laboratory of Molecular Embryology, NICHD, NIH, Bethesda, MD.
Research: Epigenetics, chromatin, biochemistry

1991-1997
Emory University, Atlanta, GA - Program in Genetics and Molecular Biology
Degree: PhD in Eukaryotic gene regulation

1987-1991
Miami University, Oxford, OH
Degree: B.A. in Microbiology

Molecular Mechanisms of Facioscapulohumeral Muscular Dystrophy (FSHD) Pathology

FSHD is the most prevalent myopathy afflicting women, men, children and adults of all ages. FSHD is an autosomal dominant disease marked by slow but progressive atrophy in specific muscle groups in the face, upper arms, abdomen, hip girdle, and legs with individuals often showing bilateral asymmetry in muscle weakness. There is a wide range in both the age of disease onset and clinical severity, from the extremely severe infantile form (IFSHD), to the more common young adult onset FSHD manifesting in the second or third decade, to the individuals who show symptoms only much later in life, if ever. Initial symptoms often causing one to seek clinical help are difficulty raising ones arms above shoulder level, facial weakness and foot drop. Additional non-muscular symptoms that appear later in the disease progression include high-frequency hearing loss in more than half of all diagnosed cases, and vision problems in ~1% of patients. With many FSHD patients becoming wheelchair-bound as young adults, the personal, social, and economic costs of this disease are enormous, and no effective therapies exist.

FSHD is a genetic disease linked to chromosome 4q35 with a strong epigenetic component (Figure 1). FSHD research has now entered an important new stage as the DUX4 gene has emerged from studies in multiple laboratories, including our own, as the near consensus FSHD candidate gene whose misexpression is necessary for pathology. The DUX4 gene is present in numerous copies in the genome as each 3.3kb repeat unit of a D4Z4 repeat array contains a DUX4 gene and D4Z4 arrays are found in several places in the genome. However, only the DUX4 gene in the distal D4Z4 repeat of the 4q35 subtelomeric array can stably express pathogenic transcripts. A pathogenic change of the epigenetic status of the 4q35 D4Z4 array, predominantly caused by large deletions within the repeats and rarely by mutations in certain genes affecting DNA methylation, leads to a relaxation of the array and aberrant DUX4 expression and alternative mRNA splicing. The current evidence supports a model in which aberrant stable expression of the DUX4 mRNA splicing variant, termed DUX4-fl (fl = full-length), in skeletal muscle is required, but not necessarily sufficient, for FSHD pathology. This pathogenic mRNA encodes a transcription factor, DUX4-FL, whose expression leads to additional aberrant expression of downstream genes in FSHD muscle. Thus, there are a number of potential targets for therapy development.

My lab has several FSHD research projects: 1) investigating the epigenetic and genetic regulation of DUX4 gene expression and alternative mRNA splicing, 2) investigating additional FSHD candidate genes and transcripts that may be involved in pathology either in concert with or independent of DUX4-fl, 3) generating animal and cell culture models of FSHD using mice, Drosophila, C. elegans and human myogenic cultures, and 4) developing therapeutic strategies to target DUX4-fl mRNA and protein expression and function.

Figure 1: FSHD1 and FSHD2 are linked to epigenetic relaxation of the chromatin at chromosome 4q35 D4Z4 macrosatellite repeat array.
Each D4Z4 repeat unit encodes exons 1 and 2 of the DUX4 gene. At least one D4Z4 repeat, combined with an “A” type subtelomere, is required for FSHD. The “A” type subtelomere encodes a third exon containing a polyadenylation signal that is spliced onto and stabilizes the DUX4 mRNA when transcribed from the terminal D4Z4 repeat. *DUX4-fl mRNA and protein have been detected in a small number of control biopsies and myogenic cell cultures; however, the level is significantly lower than what is found in FSHD. Of note, a number of individuals (estimated up to 1-3%) in the general population have FSHD1-sized deletions and do not exhibit clinical symptoms of FSHD. Their expression levels of DUX4-fl in muscle are currently unknown.

Department of Cell and Developmental Biology
Wellstone Program