Response to Kidney Injury Is Epigenetically Regulated Through the Activation of Bivalent Genes Driving Inflammation and Immune System Activation

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Background: Bivalent genes are regions of epigenetically modified nucleosomes that carry both H3K4me3 and H3K27me3 and exist in a poised transcriptional state, ready for activation or repression depending upon stimuli. While these regions have been well-established as determining cell lineage during early development, the role of bivalency has not been characterized in renal injury. In this work, we demonstrate that activated bivalent genes are associated with upregulation of genes that drive the response to ischemia reperfusion injury (IRI) in the mouse. Methods: CUT&RUN using antibodies to H3K4me3 and H3K27me3 was carried out on normal mouse kidneys and kidneys 3 days after IRI. Per-gene scores were calculated for each histone mark by integrating the signals from CPM normalized aligned reads across relevant genomic regions and calculating log fold enrichment with respect to off-target IgG background signal. Expression response to IRI was determined using RNA from mouse kidney tissue 3 days after sham or IRI surgeries. Results: Our CUT&RUN analysis identified 1550 bivalent gene candidates with enrichment of both H3K27me3 and H3K4me3 in normal kidneys. Filtering bivalent genes for increasing H3K4me3 signal and decreasing H3K27 score, we found that 12% (164/1550) of these bivalent genes were activated in response to IRI. Upon cross-referencing activated bivalent genes with RNAseq expression data, we found 78% (82/105) epigenetically activated genes had low expression in normal kidneys and increased expression in response to IRI. Pathway analysis of all bivalent genes in the normal kidney returned GO terms related to development and morphogenesis. In contrast, after restricting our pathway analysis to bivalent genes that were epigenetically activated after IRI, results were dominated by pathways related to inflammatory response and immune system activation. Conclusion: Our work suggests that part of the inflammatory response to renal injury is regulated by epigenetic activation of specific bivalent genes that are transcriptionally poised in the kidney. This discovery reveals a critical epigenetic control point that may be therapeutically targeted to reduce damaging outcomes following kidney injury. Funding: NIDDK Support

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