DUX4-Induced Histone Variants H3.X and H3.Y Mark DUX4 Target Genes for Expression
This week we profile a recent publication in Cell Reports from the laboratory of Dr. Stephen Tapscott at Fred Hutch.
Photo courtesy of Robert Hood/Fred Hutch
Front row from left to right: Rebecca Resnick, Jessica Kumar, Stephen Tapscott, Amy Campbell, Danielle Hamm
Back row from left to right: Sean Bennett, Nick Sutliff, Andrew Smith, Amy Spens, Sean Shadle
Historically the lab has focused on the molecular mechanisms of cell specification and differentiation. Recent work has focused on the DUX4 transcription factor encoded by a retrogene in repetitive DNA that was previously considered “junk” DNA. Our work, and the work of others, showed that this retrogene has a critical role in normal development and its mis-expression in skeletal muscle causes a muscular dystrophy, facioscapulohumeral dystrophy (FSHD).
What is the significance of the findings in this publication?
The transcription factor DUX4 is briefly expressed at the 4-cell stage in human embryos, where it regulates a portion of the first wave of gene expression. DUX4 is also expressed briefly in some stem cell populations, such as ES or iPS cells where it might regulate the transition into the early naïve state of pluripotency. One important question has been whether the brief expression of this transcription factor leaves a longer-term memory in the cell that might maintain aspects of the early pluripotent state for a period of time after the expression of DUX4. In this publication, we showed that DUX4 induces the expression of the histone variants H3.X and H3.Y. These histones become incorporated into the chromatin of DUX4 induced genes and create a chromatin memory of their activation by DUX4, manifesting in greater perdurance of expression and greater sensitivity to re-activation. Although the biological consequences of this have yet to be tested in development and stem cells, we did show that H3.X and H3.Y induction by DUX4 were necessary to amplify DUX4 signaling in FSHD muscle cells, providing support for this model and a role for these histone variants in this muscular dystrophy.
What are the next steps for this research?
When DUX4 is expressed in the early embryo, there is a significant epigenetic reprogramming that contributes to the establishment of a pluripotent state. We suspect that the induction of the H3.X/Y histone variants are one part of this early reprogramming and that DUX4 might also have other mechanisms to reprogram the cell to a pluripotent epigenetic state. One priority going forward will be to fully characterize the long-term epigenetic consequences of a brief expression of DUX4 and subsequent role in stem cell biology and possibly human disease. In regard to FSHD, as noted above, we have evidence that the DUX4-induced histone variants amplify the DUX4 program in FSHD muscle and it will be important to determine whether suppressing their expression might represent a therapeutic intervention. Recently, together with the Bradley lab at the Fred Hutch, we also showed that DUX4 is expressed in a wide-variety of human cancers where it might help the cancer to evade the immune system. An important question we need to address is whether epigenetic mediators of DUX4 activity identified in the current study might also have a role in cancer growth or response to therapies.
This work was funded by:
This work was supported by the National Institutes of Health (NIAMS R01AR045203, NINDS P01NS069539 and F31NS101773), and the Friends of FSH Research.