The response to kidney injury is epigenetically regulated through the activation of bivalent genes

Epigenetic regulation through histone modifications plays a crucial role in driving cellular state transitions. Regulating gene transcription through bivalency, the co-occurrence of activating histone H3 lysine 4 trimethylation (H3K4me3) and repressive histone H3 lysine 27 trimethylation (H3K27me3) histone marks, drives cell fate in development; however, its role in kidney injury is not known. Here, we investigated bivalent gene activation in the adult male <i>Mus musculus</i> kidney following ischemia-reperfusion injury (IRI). We developed and validated a novel per-gene scoring method for identifying bivalent domains from CUT&RUN (Cleavage Under Targets and Release Using Nuclease) data. Our analysis revealed that bivalent genes in the mature kidney substantially overlap with known embryonic bivalent domains. Following IRI, a subset of bivalent genes became activated, defined by a loss of H3K27me3, enrichment of H3K4me3, and a corresponding increase in gene transcription. Activated bivalent genes were differentially expressed in kidney epithelial cells and strongly enriched for pathways involving inflammation and fibrosis. To uncover the regulatory mechanism associated with activated bivalent genes, we identified key transcription factors linking these genes which converged on the pioneer transcription factor, <i>Spi1</i>. We demonstrated that <i>Spi1</i> targets are differentially expressed in both mouse and human kidney epithelial cells after injury and preferentially depleted of H3K27me3 and gain H3K4me3 enrichment after IRI, supporting its role in mediating the epigenetic switch. Our findings reveal a common epigenetic mechanism where transcription factors, acting on bivalent chromatin, contribute to inflammatory and fibrotic responses to kidney injury. This suggests that the progression from acute to chronic kidney injury is an active, transcriptionally driven failure of repair that is epigenetically mediated by histone modifications.<b>NEW & NOTEWORTHY</b> We performed the first identification of bivalent domains in the adult mouse kidney. We identified bivalent genes that, when activated after kidney injury, drive inflammation, proliferation, and fibrosis. Activation of bivalent genes is coordinated by transcription factors such as <i>Spi1</i>. Our research not only provides a valuable database of bivalent genes in the kidney but also demonstrates that activation of bivalent genes is crucial for the progression from acute to chronic kidney injury.