Progress Update: DUX4-induced mechanisms contributing to FSHD pathogenesis

Mentor: Stephen J. Tapscott, MD, PhD
See grant DUX4-induced mechanisms contributing to FSHD pathogenesis

My research is primarily focused on understanding the molecular mechanisms that occur in FSHD. I am trying to answer fundamental questions about DUX4 – the disease causing factor of FSHD – and how it functions inside the cell. DUX4 is a transcription factor that binds DNA and turns genes on. We find that DUX4 activates many genes associated with early development, genes that are off in healthy muscle cells. DUX4 itself is scarcely present in FSHD muscle cells and expressed at very low levels; however, this low-level expression is highly toxic to muscle cells. We believe this is because DUX4 triggers prolonged cellular responses that continue to act in the cell long after DUX4 is gone. My research has discovered multiple long-lived mechanisms by which DUX4 acts to disrupt normal cellular function when mis-expressed in muscle, including:

  1. (1) DUX4 activates several factors that help unpackage or “open” the DNA, allowing DUX4 to bind and activate genes. Current work is focused on determining how and where these changes to the DNA structure occur. By targeting factors activated by DUX4 that alter the DNA structure, we could potentially limit the effects of DUX4 by keeping DNA “closed” at genes that should remain off in muscle cells.
  2. (2) We have also found that DUX4 induces double-stranded RNA molecules (dsRNAs) not normally present in healthy cells. We investigated the nature of the dsRNAs generated by DUX4 and the consequences of their accumulation. dsRNAs can trigger cell stress pathways and disrupt normal cell function, ultimately lead to cell death. Current work is focused on characterizing how these mechanisms disrupt cell function and cause cell toxicity in FSHD.

These data provide several approaches to the challenge of creating an FSHD therapeutic. Strategies that inhibit downstream factors induced by DUX4 that produce toxic cellular responses could aid in stopping FSHD disease progression.