In the Dilworth Lab, our research is focused on how muscle
stem cells work to regenerate muscle tissue and how the environment they live
in can influence their ability to repair muscle damage. This capacity to
regenerate is necessary to replace, grow and repair our skeletal muscle
throughout our lives. When something goes wrong with the function of these stem
cells (called satellite cells), muscle tissue wastes away, which is the case
for people suffering from muscular dystrophies. And as we age, maintaining
muscle mass becomes increasingly difficult, also a result of changes in the
effectiveness of our satellite cells. We are trying to address both of these
areas by exploring how these stem cells respond to epigenetic influences, and how
we can modify the muscle environment in which these satellite cells live to
improve their regenerative function.
The idea behind epigenetics is that the hardwired DNA blueprint
in our cells can be influenced by the environment to shape our body's destiny. Indeed,
how our muscles are used (active versus sedentary) and nourished will make a
difference in how our DNA blueprint is utilized within the stem cells. We are
particularly interested in how epigenetic influences can change the way our DNA
is packaged within the cell, a process that greatly controls access to specific
genes within our hardwired genetic code. Different cells in the body need
access to different parts of our DNA. This DNA access is critical for cells to
be healthy and work properly as it allows the proper genes for a specific cell type to be turned on.
We are continually expanding our understanding of the genes necessary
to maintain muscle stem cells in a healthy, functional state. The goal of the Dilworth Lab is to understand
why the genes that maintain stem cells in a healthy state sometimes get turned
off and how we can use epigenetics to turn these genes back on, so our satellite
cells can function properly and effectively throughout our lifetime.
H. Faralli, C. Wang, A. Benyoucef, S.
Sebastian, L. Zhuang, A. Chu, C. Palii, C. Liu, B.
Camellato, M. Brand, K. Ge, and F.J. Dilworth. H3K27-demethylase activity of UTX/KDM6A is
essential for skeletal muscle regeneration. Journal of Clinical
Investigation 126: 1555-1565, 2016.
M. Cassano, E. Planet, S.Sebastian, S.M. Jang, G.
Sohi, J. Choi, H.D. Youn, F.J.
Dilworth*, and D. Trono*. KAP1 functions as a phosphorylation-inducible activator of MyoD function
during skeletal muscle differentiation. Genes & Dev 29:
2015. *Co-corresponding authors
S. Sebastian, H. Faralli, Z. Yao, P.
Rakopoulos, C. Palii, Y. Cao, K. Singh, Q-C. Liu, A. Chu,
A. Aziz, M. Brand, S.J. Tapscott, and F.J. Dilworth. Tissue-specific splicing of a ubiquitously expressed
transcription factor is essential for muscle differentiation. Genes & Dev 27: 1247-1259, 2013.
Q-C. Liu, X. Zha, H. Faralli,
H. Yin, C. Louis-Jeune, E. Perdiguero, E. Pranckeviciene, P.
Munoz-Canoves, M. Rudnicki, M. Brand, C. Perez-Iratxeta, and F.J. Dilworth. Comparative expression
profiling identifies differential roles for Myogenin and p38a MAPK signaling in myogenesis. J Mol Cell Biol. 4 : 386-397, 2012.
S. Seenundun, S. Rampalli, Q-C. Liu, A.
Aziz, C. Palii, S.H. Hong, A. Blais, M. Brand, K. Ge, F.J. Dilworth. UTX-mediated
demethylation of H3K27me3 at muscle-specific genes during myogenesis. EMBO
Journal 29: 1401-1411, 2010.
S. Rampalli, L. Li, E. Mak, K. Ge, M.
Brand, S.J. Tapscott, and F.J. Dilworth. p38 MAPK signaling pathway regulates
recruitment of Ash2L-containing methyltransferase complexes to specific genes
during differentiation. Nature Struct Mol
Biol 14: 1150-1156, 2007.