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Progress Report: Targeting Epigenetic Silencing of the 4qD4Z4 repeat array in FSHD

Posted by George Shaw on January 31, 2014

by Jong Won Lim, postdoctoral fellow
Mentors: Galina Filippova, PhD and Stephen Tapscott, MD, PhD
See grant Targeting Epigenetic Silencing of the 4qD4Z4 repeat array in FSHD

My research goal is to identify silencing mechanisms that prevent DUX4, the FSHD causing gene, from being upregulated in non-disease condition. During the past few years significant research progress in characterization of DUX4 has been made, but it is still unclear how this gene is regulated and why it is upregulated in FSHD muscle. Better understanding of the DUX4 gene regulation will help us to identify efficient therapeutic targets to block muscle wasting caused by DUX4 expression in FSHD condition and to promote regeneration of muscle tissue. Here I propose that non-coding transcripts and small RNAs expressed from the D4Z4 arrays mediate DUX4 epigenetic silencing. We identified several small RNAs at the non-coding regions of the D4Z4 repeats that efficiently decreased DUX4 expression and increased repressive epigenetic marks at their target sites. To understand the mechanism underlying function of these small RNAs, we are defining which components of the small RNA processing machinery and which RNA transcripts derived from the D4Z4 arrays are the key players in the epigenetic regulation of the DUX4 gene. Based on our research data, we will determine the most efficient types of therapeutic molecules and their delivery methods that will allow us to induce long-term DUX4 epigenetic silencing in FSHD condition.