JMJD3 as a transducer of environmental signals in the regenerative niche

About This Grant

Project Summary/Abstract Muscle stem cells (MuSCs) provide myofibers with a robust tool for regeneration after injury. The efficiency of this muscle regenerating capacity depends upon the ability of MuSCs to integrate signals emanating from complementary cell types within the damaged muscle. Unfortunately, integration of these signals is often disrupted in disease, which results in a functional depletion of the MuSC population. MuSCs are still present, but they are not able to respond to regenerative cues from the environment. Although substantial evidence supports a role for epigenetic enzymes in orchestrating the transcriptional programs necessary for MuSCs to respond to niche-derived cues, how these enzymes enable MuSCs to actively shape the regenerative environment— particularly under inflammatory conditions—remains poorly understood. Our preliminary studies indicate that the H3K27 demethylase JMJD3 is rapidly induced in MuSCs after injury and regulates key genes that facilitate communication with immune cells, allowing MuSCs to exit quiescence and support tissue repair. Loss of JMJD3 in MuSCs leads to aberrant cytokine expression and excessive accumulation of inflammatory macrophages, suggesting that JMJD3 enables MuSCs not only to respond to signals but also to broadcast critical cues that help calibrate the immune response. Despite this emerging evidence, the underlying mechanisms through which JMJD3 governs MuSC–immune cell communication remain unknown. The overall objective of this project is to define the JMJD3-dependent transcriptional and epigenetic programs that allow MuSCs to modulate the inflammatory niche and initiate regeneration. We hypothesize that JMJD3 integrates signals from the regenerative environment by removing repressive H3K27me3 marks at immunomodulatory genes, permitting their expression to shape immune cell behavior and ensure efficient repair. We will address this through two aims: Aim 1: Use TEA-seq, a trimodal single-cell approach, to uncover the signaling pathways by which MuSCs regulate the magnitude and duration of the immune response to muscle injury. Aim 2: Determine how JMJD3-mediated H3K27 demethylation integrates niche-derived signals to control inflammatory resolution, testing whether modulation of H3K27me3 levels governs expression of MuSC immunomodulatory genes. Successful completion of these studies will elucidate how JMJD3 enables MuSCs to coordinate the inflammatory landscape necessary for regeneration, fundamentally advancing our understanding of how stem cells navigate and shape complex tissue environments. By revealing the extent to which epigenetic control of MuSC–immune communication influences regeneration, this work will provide a critical foundation for future efforts to fine-tune inflammation in muscle-wasting diseases.