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JMJD3 activated hyaluronan synthesis drives muscle regeneration in an inflammatory environment

Muscle stem cells (MuSCs) reside in a specialized niche that ensures their regenerative capacity. Although we know that innate immune cells infiltrate the niche in response to injury, it remains unclear how MuSCs adapt to this altered environment for initiating repair. Here, we demonstrate that inflammatory cytokine signaling from the regenerative niche impairs the ability of quiescent MuSCs to reenter the cell cycle. The histone H3 lysine 27 (H3K27) demethylase JMJD3, but not UTX, allowed MuSCs to overcome inhibitory inflammation signaling by removing trimethylated H3K27 (H3K27me3) marks at the Has2 locus to initiate production of hyaluronic acid, which in turn established an extracellular matrix competent for integrating signals that direct MuSCs to exit quiescence. Thus, JMJD3-driven hyaluronic acid synthesis plays a proregenerative role that allows MuSC adaptation to inflammation and the initiation of muscle repair. Description JMJD3 primes stem cells for inflammation After muscle injury, muscle stem cells must coordinate with immune cells in the inflamed tissue to ensure efficient repair. Nakka et al. identified an essential role for the epigenetic enzyme KDM6B/JMJD3 in establishing the communication between muscle stem cells and infiltrating immune cells during muscle repair (see the Perspective by Gabellini). They found that, in response to injury, removal of the transcriptionally repressive histone H3K27me3 modification by KDM6B/JMJD3 allows muscle stem cells to produce hyaluronic acid that is then incorporated into the extracellular matrix. This remodeling of the extracellular matrix allows the muscle stem cell to receive signals from the infiltrating immune cells that initiate regeneration. —SMH and BAP A histone demethylase initiates muscle repair by removing H3K27me3 marks at genes needed to dampen an inflammatory block to stem cell function.