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Background  The progression rate of CKD varies substantially among patients. The genetic and epigenetic contributions that modify how individual patients respond to kidney injury are largely unknown. Emerging evidence has suggested that histone H3 K79 methyltransferase Dot1l has an antifibrotic effect by repressing  Edn1 , which encodes endothelin 1 in the connecting tubule/collecting duct.    Methods  To determine if deletion of the  Dot1l  gene is a genetic and epigenetic risk factor through regulating  Edn1,  we studied four groups of mice: wild-type mice, connecting tubule/collecting duct–specific  Dot1l  conditional knockout mice ( Dot1l AC  ),  Dot1l  and  Edn1  double-knockout mice ( DE AC  ), and  Edn1  connecting tubule/collecting duct–specific conditional knockout mice ( Edn1 AC  ), under three experimental conditions (streptozotocin-induced diabetes, during normal aging, and after unilateral ureteral obstruction). We used several approaches (colocalization, glutathione S-transferase pulldown, coimmunoprecipitation, yeast two-hybrid, gel shift, and chromatin immunoprecipitation assays) to identify and confirm interaction of Dot1a (the major  Dot1l  splicing variant in the mouse kidney) with histone deacetylase 2 (HDAC2), as well as the function of the Dot1a-HDAC2 complex in regulating  Edn1  transcription.    Results  In each case,  Dot1l AC   mice developed more pronounced kidney fibrosis and kidney malfunction compared with wild-type mice. These  Dot1l AC   phenotypes were ameliorated in the double-knockout  DE AC   mice. The interaction between Dot1a and HDAC2 prevents the Dot1a-HDAC2 complex from association with DNA, providing a counterbalancing mechanism governing  Edn1  transcription by modulating H3 K79 dimethylation and H3 acetylation at the  Edn1  promoter.    Conclusions  Our study confirms  Dot1l  to be a genetic and epigenetic modifier of kidney fibrosis, reveals a new mechanism regulating  Edn1  transcription by Dot1a and HDAC2, and reinforces endothelin 1 as a therapeutic target of kidney fibrosis.

Loss of Histone H3 K79 Methyltransferase Dot1l Facilitates Kidney Fibrosis by Upregulating Endothelin 1 through Histone Deacetylase 2