Progress Update: Targeting DUX4 in the 4qD4Z4 repeat array in FSHD

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 multiple sense and antisense transcripts and small RNAs expressed from the D4Z4 arrays mediate DUX4 silencing. We made significant progress on this project. We identified several small RNAs that efficiently decreased DUX4 expression in FSHD cells and determined some of the key players involved in DUX4 down regulation by these small RNAs (a manuscript describing these findings is been prepared for publication). To further understand the mechanisms underlying the function of the D4Z4 derived small RNAs, as a next step, we are defining which D4Z4 RNA transcripts are involved in DUX4 regulation. Based on our research data, we will determine the most efficient types of therapeutic molecules and their delivery methods that will allow us to target DUX4 in FSHD condition.