Rucha Sarwade, PhD

PI/Investigator: Rucha Sarwade, PhD - Monash University, Australia
Award type: Postdoctoral fellowship
Grant Title: Investigating epigenetic silencing in Friedreich's Ataxia

Summary: 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 interferes 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 transcriptional silencing of FXN gene. This project aims to fill this critical knowledge gap and uncover sequential epigenetic events that are crucial to design 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 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) that 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.