Mutations in the gene encoding emerin (EMD) cause Emery-Dreifuss muscular dystrophy (EDMD1), an inherited disorder characterized by progressive skeletal muscle wasting, irregular heart rhythms and contractures of major tendons. The skeletal muscle defects seen in EDMD are caused by failure of muscle stem cells to differentiate and regenerate the damaged muscle. However, the underlying mechanisms remain poorly understood. Most EDMD1 patients harbor nonsense mutations and have no detectable emerin protein. There are three EDMD-causing emerin mutants (S54F, Q133H and Δ95-99) that localize correctly to the nuclear envelope and are expressed at wildtype levels. We hypothesized these emerin mutants would share in the disruption of key molecular pathways involved in myogenic differentiation. We generated myogenic progenitors expressing wildtype emerin and each EDMD1-causing emerin mutation (S54F, Q133H, Δ95-99) in an emerin-null background. S54F, Q133H, and Δ95-99 failed to rescue emerin-null myogenic differentiation, while wildtype emerin efficiently rescued differentiation. Each of these mutants disrupts binding to HDAC3. Thus, we tested another emerin mutant, M179, that specifically blocks binding to HDAC3. M179 also failed to rescue emerin-null myogenic differentiation. Collectively, these studies implicate the functional interaction of emerin with HDAC3 in the EDMD disease mechanism. RNA sequencing was done to identify pathways and networks important for emerin regulation of myogenic differentiation. This analysis significantly reduced the number of pathways implicated in EDMD1 muscle pathogenesis.
|Advisor:||Suryanarayanan, Asha, Holaska, James|
|Commitee:||Harvison, Peter, Klase, Zachary, Janetopoulos, Christopher|
|School:||University of the Sciences in Philadelphia|
|Department:||Pharmacology & Toxicology|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 81/12(E), Dissertation Abstracts International|
|Keywords:||Emerin, Myogenic differentiation, Nuclear envelope|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be