Several models have been proposed to explain FXN gene silencing. Two eminent amongst them are: 1. Formation of unusual triplex DNA structures and R-loops that interfere with the RNA pol II processivity leading to transcriptional blockage, 2. Formation of heterochromatin. While research findings are consistent with both possibilities, neither of them adequately explains the transcriptional silencing of the FXN gene. This project aims to fill this critical knowledge gap and uncover sequential epigenetic events that are crucial to designing effective treatment strategies for Friedreich’s Ataxia (FRDA). In a parallel universe, studies on plants that have a peculiar growth defect due to an intronic triplet repeat expansion led to interesting observations. This plant model shares striking parallels at the molecular level with FRDA, suggestive of potential common underlying biology. In the plant model, repeat expansion causes the accumulation of specific non-coding RNA species called siRNAs. These siRNAs lead to gene silencing by RdDM (RNA-dependent DNA methylation) -dependent epigenetic modifications. Interestingly, repeat expansion-associated plant phenotype was rescued by mutations in enzymes that can cause post-translational modification of proteins. Excitingly, HETEROCHROMATIN PROTEIN 1 (HP1), which has been shown to be associated with epigenetic silencing in FRDA, is known to be affected by such post-translational modifications. Dr. Sarwade hypothesizes that RNA-mediated epigenetic changes occurring at the FXN locus are maintained by protein modifications of chromatin modifiers such as HP1. Through this fellowship, Dr. Sarwade intends to test whether the learnings from the plant research also translate to FRDA, using cell lines derived from patients.
Postdoctoral Research Award | Mechanism or Pathway of Disease
Investigating epigenetic silencing in Friedreich’s Ataxia
Grant Awarded | Jan 2022
Rucha Sarwade, PhD
Monash University, Australia
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The FARA Grant Program is proud to award a Postdoctoral Research Award to Rucha Sarwade, PhD at Monash University, Australia.
Co-sponsor: fara Australia