Project 2: Repeat derepression and RNA-mediated toxicity in FSHD

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PROJECT 2: Repeat derepression and RNA-mediated toxicity in FSHD Abstract FSHD is caused by somatic derepression of the normally transcriptionally silent D4Z4 locus and subsequent expression of the disease gene DUX4. The broad and long-term goal of this project is to identify molecular pathways downstream of D4Z4 derepression that may be targeted to slow disease progression or improve muscle function. The major hypothesis of this project is that repetitive and other aberrant RNAs contribute to DUX4 cytotoxicity and modify FSHD severity. The specific goal of the project is to identify the mechanistic origins of aberrant RNA production and cytotoxicity, and determine whether these toxic RNAs modify FSHD penetrance. This will be accomplished by: Aim 1, Determine the molecular mechanisms of DUX4-mediated inhibition of RNA surveillance; Aim 2, Determine the subset of DUX4-induced RNAs that are actively translated, and test whether these aberrant RNAs produce abnormal proteins or novel peptides in DUX4-expressing cells; Aim 3, Determine whether genetic variation influences repetitive RNA expression to modify FSHD penetrance. Together, these aims will identify mechanisms that promote stable expression of repetitive and other aberrant RNAs, thereby contributing to DUX4 toxicity and acting as a novel modifier of FSHD penetrance. The significance of these studies is that they will identify molecular pathways downstream of D4Z4 derepression that mediate DUX4 toxicity and contribute to variable penetrance of FSHD. The health relatedness is that RNA-mediated mechanisms of toxicity may provide opportunities for therapeutic intervention downstream of D4Z4 derepression.