Posted by Friends of FSH Research on Jun 12, 2020
Investigator: Danielle C Hamm PhD
Mentor: Stephen J Tapscott MD PhD
See grant Analysis of histone demethylases as candidate targets for FSHD therapeutics
This award is supported by the Friends of FSH Research in coordination with the Wellstone Muscular Dystrophy Research Center in Seattle. This award supports areas of FSHD research focused around DUX4 biology. The DUX4 gene encodes a transcription factor normally expressed in early embryo development. Chromatin-mediated repression prevents DUX4 expression in most other tissues. Loss of this repression causes facioscapulohumeral muscular dystrophy (FSHD) due to mis-expression of DUX4 in skeletal muscle. Many chromatin factors regulate DUX4 expression and understanding the involved regulators may yield new and effective therapies for FSHD.
Through the supported research we find that DUX4 activates several chromatin factors that regulate gene expression in FSHD. The histone variants H3.X and H3.Y are directly activated by DUX4 and further increase DUX4 expression and amplify DUX4-target gene expression in FSHD muscle cells. Additionally, DUX4 activates a histone lysine demethylase enzyme that epigenetically regulates chromatin structure and gene expression. While we find that this demethylase does not impact DUX4 expression, it does contribute to the DUX4 activated program in FSHD muscle. DUX4 activation of this histone demethylase causes increased gene expression from repetitive DNA sequences. Such DNA elements constitute an abundant yet enigmatic part of the human genome and their biological role is still elusive. In addition to understanding the mechanism of their activation, we want to know whether the de-repression of these DNA elements contributes to the disease progression in FSHD.
Note that the Wellstone co-funds this grant.
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