Researchers Identify a New Compound that Inhibits the Activity of DUX4
By Alec DeSimone, PhD
University of Massachusetts Medical School
Led by a team at the University of Minnesota, Minneapolis, researchers have identified a new compound that inhibits the activity of DUX4, implicated as the root cause of facioscapulohumeral muscular dystrophy (FSHD). The compound provides resistance to DUX4’s pathogenic effects. It does not affect DUX4 itself, but a second protein, P300, which the authors have previously shown to be essential for DUX4 to exert its toxic effects.
P300 belongs to a class of proteins known as histone acetyltransferases, or HATs, which help to regulate genes by modifying the histones. (Histones are spool-like structures that DNA is wrapped around.) Histones allow specific regions to “open” so that the genetic code in those regions can be read out by the cell. The researchers showed that through its interaction with P300, DUX4 causes these signals to be inappropriately and massively spread across the genome. This results in gene expression that is uncontrolled and damaging to the cell.
The new compound, which the authors name iP300w (inhibitor of P300), belongs to a class of HAT inhibitor molecules that prevent this DUX4-driven, rogue activity. In cells grown in culture, the researchers observed that iP300w prevented DUX4 from causing this mass modification of the genome. Furthermore, the researchers observed that some DUX4-driven genes were also reduced by iP300w. Importantly, both of these changes were correlated with increased survival of the iP300w-treated cells. The upshot: inhibiting HAT activity may potentially be a strategy to treat FSHD.
The researchers then went on to test this possibility by treating DUX4-expressing mice with iP300w. They found that treated mice showed a similar inhibition of DUX4 activity as well as reduced loss of muscle and a reduction in other markers of muscle disease.
The results presented in this study have important implications for FSHD research. iP300w can prevent cell death and reduce other indicators of pathology in both cell culture and mouse models of FSHD. This means it provides strong evidence that targeting P300/HATs is a new and unexplored pathway that can be targeted for therapeutic development. This should attract much future work on the subject.
There is a great deal to be done before the work presented here can be translated into a viable treatment. Compounds that inhibit HAT and are suitable for drug development have yet to be identified. What’s more, P300 and other HATs are very important proteins that are critical regulators of a wide array of biological activities that are unrelated to FSHD, so “more animal studies, particularly long-term animal studies will be necessary before iP300w can be tested on humans,” notes Michael Kyba, PhD, senior author of the new study.
However, as the authors noted in their paper, this work does demonstrate that preventing DUX4 from causing large-scale changes in P300’s activity is a viable approach to drug development. This raises the possibility of investigating therapeutic approaches that provide more targeted ways of preventing DUX4 from interacting with P300 and affecting its activity.
A novel P300 inhibitor reverses DUX4-mediated global histone H3 hyperacetylation, target gene expression, and cell death. Bosnakovski D, da Silva MT, Sunny ST, Ener ET, Toso EA, Yuan C, Cui Z, Walters MA, Jadhav A, Kyba M. Sci Adv. 2019 Sep 11;5(9):eaaw7781.