of Cell and Developmental Biology /
Associate Professor - University of Massachusetts Medical School
Research: Epigenetics; Muscle development and disease, FSHD; Rett Syndrome
Affiliate Investigator - Sen. Paul D. Wellstone Cooperative Research
Center for FSHD
Principal Scientist - Boston Biomedical Research Institute
Assistant Professor - Department of Cell and Developmental Biology - University
of Illinois at Urbana-Champaign
Postdoctoral fellow - Laboratory of Molecular Embryology, NICHD, NIH, Bethesda,
MD. Mentors: Alan P. Wolffe and Yun-bo Shi
Research: Epigenetics, chromatin, biochemistry
Emory University, Atlanta, GA - Program in Genetics and Molecular Biology
Degree: PhD in Eukaryotic gene regulation
Miami University, Oxford, OH
Degree: B.A. in Microbiology
Molecular Mechanisms of Facioscapulohumeral Disease (FSHD)
FSHD is the most prevalent muscular dystrophy indiscriminately 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
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 developing 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 large D4Z4 macrosatellite arrays are found in several places in the genome. However, only the
DUX4 gene in the distal D4Z4 repeat of a permissive 4q35 subtelomeric array can
stably express pathogenic transcripts. 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 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. Expression of DUX4-fl per se is not necessarily causal for FSHD as healthy unaffected individuals occasionally express DUX4-fl mRNA and protein in muscle, albeit at much lower levels than seen in FSHD muscle. This suggests a quantitative model for DUX4-fl expression leading to FSHD pathology whereby low expression levels are tolerated by certain individuals and higher levels beyond a threshold result in FSHD pathology.
The primary driver of FSHD pathology is the epigenetic status of a permissive (A type subtelomere) 4q35 D4Z4 macrosatellite array. Pathogenic changes in the epigenetic
status of the 4q35 D4Z4 array occur through several mechanisms including large deletions within
the repeats (FSHD1), mutations in genes affecting DNA methylation and heterochromatin structure (FSHD2), or a combination of both. Regardless of the mechanism for dysregulation, these epigenetic changes result in the increased aberrant expression of DUX4-fl.
Interestingly, a number of seemingly healthy individuals have been found
to possess the FSHD1 genetic lesion combined with a permissive 4q subtelomere yet
show no clinical manifestation of the disease. Myogenic cells from
these individuals show a wide range of DUX4-fl expression from very low,
similar to healthy individuals, to levels equivalent to those found in
clinically affected FSHD individuals. In addition, we have found that the epigenetic relaxation of the D4Z4 array is highly variable among genetically FSHD1 individuals, including those clinically affected as well as disease non-manifesting subjects. This indicates the existence of
multiple modifier genes functioning at two levels; upstream, regulating
the level of DUX4-fl expression (epigenetic modifiers) and downstream,
regulating the function of DUX4-fl. Thus, in addition to DUX4-fl itself, there are a number of additional potential targets for therapeutic development.
Drs. Peter and Takako Jones are a husband-wife team and function effectively as Co-PIs in the lab. Our 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 the epigenetic relaxation of the chromatin
at a permissive 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 a permissive “A” type subtelomere is required to develop FSHD. The permissive “A” type subtelomere encodes a third exon containing a polyadenylation signal
that is spliced onto the DUX4 mRNA, thus stabilizing only the DUX4 message 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.
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.
of Cell and Developmental Biology