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In vivo model to validate drugs targeting DUX4 enhancer/promoter activity

In vivo model to validate drugs targeting DUX4 enhancer/promoter activity

Budget

  • Amount awarded: US$50,000 (Year 1)
  • FSHD Canada Foundation Contribution: US$25,000 (Year 1)

Timeline

  • 2 Years, US$50,000 per year

Lay Abstract

Principle Investigator: Yosuke Hiramuki (at Peter Jone’s laboratory)

Research Institution: University of Nevada

DUX4 is normally expressed in testis in healthy individuals and aberrantly expressed in specific
skeletal muscles of FSHD patients. Previous work in our lab identified two DUX4 enhancer
regions, called DUX4 myogenic enhancers (DME), that regulate DUX4 expression in cultured
human myogenic cells and contain putative binding sites for testis and myogenic regulatory
factors (Himeda et al., 2014). To further investigate whether these DME regions have
developmental and tissue specific enhancer activity, we generated transgenic mice, pJ2-
CreEGFP, that express CreEGFP under control of DUX4 enhancers and promoter (see Fig).
When crossed with R26NZG reporter mice, which express LacZ in response to Cre expression
(Yamamoto et al., 2009), we are able to determine when the DMEs are active by assaying for
LacZ expression using X-Gal. Intriguingly, in three independent lines, LacZ-positive cells were
detected mainly in limb and face muscles at E13.5, regions affected in FSHD. We also detected
expression of LacZ in adult testis and tibialis anterior muscles. These results suggest that the
DUX4 enhancer/promoter in these mice is functioning similarly to what is known about DUX4
expression profiles in human. Here, we seek to validate the pJ2-CreEGFP mouse model for
characterizing putative FSHD therapeutics targeting activation of DUX4 expression. Current
systems have limitations in respect to effects of chronic dosing and potential activation of
compensatory mechanisms. This system would complement current drug validation studies and
provide important insight to long term efficacy of these emerging FSHD therapeutics.

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