Abstract
Renal fibrosis is a histological manifestation that occurs in almost every type of chronic kidney disease. Histone variant H3.3 and its chaperone, histone cell cycle regulation defective homolog A (HIRA), serve as epigenetic marks that regulate transcriptional activity. In this study, we assessed the roles of histone H3.3 and HIRA in unilateral ureteral-obstruction (UUO) mice. In UUO mice, the levels of histone H3.3 and HIRA were significantly upregulated in the kidneys. These upregulated levels were decreased by a TGF-β1 neutralizing antibody. TGF-β1 induced histone H3.3 and HIRA expression in vitro via a Smad3-dependent pathway in normal rat kidney (NRK)−52E cells. Additionally, knockdown of HIRA expression decreased histone H3.3 expression and fibrogenesis in NRK-52E cells after TGF-β1 stimulation. Chromatin immunoprecipitation analysis revealed that promoters of fibrosis-related genes were immunoprecipitated with both histone H3.3 and HIRA in NRK-52E cells. Lastly, in human kidney biopsies from patients diagnosed with IgA nephropathy, histone H3.3 and HIRA immunostaining correlated positively with areas of fibrosis and estimated glomerular filtration rate. In conclusion, TGF-β1 induces expression of histone H3.3 and HIRA, which regulates expression of fibrosis-related genes.
Highlights
Chronic kidney disease (CKD) is estimated to occur in 13–15% of the population in developed countries[1,2] and it exerts a substantial socioeconomic burden worldwide
We examined the regulation of histone H3.3 and HIRA by transforming growth factor (TGF)-β1 in vivo and in vitro
Inhibition of HIRA suppresses TGF-β1-induced fibrogenesis along with a decrease in histone H3.3 expression. Both HIRA and histone H3.3 immunoprecipitate with promotors of genes involved in fibrosis, such as Col1a1, connective tissue growth factor (Ctgf), Pai[1] and Acta[2]
Summary
Chronic kidney disease (CKD) is estimated to occur in 13–15% of the population in developed countries[1,2] and it exerts a substantial socioeconomic burden worldwide. To suppress the progression of CKD, inhibitors of the renin-angiotensin-aldosterone system have been developed[10]. We demonstrated that TGF-β1-induced histone H3 lysine 4 monomethylation (H3K4me1) promotes the transcriptional activity of genes involved in fibrosis through the induction of SET domain–containing lysine methyltransferase 7/9 (SET7/9)[16]. SET7/9 possibly affects all histone tails of histone H3; the epigenetic mechanism by which TGF-β1 regulates transcriptional activity of fibrosis-related genes is not fully understood. That histone H3.3 overlaps with H3K4me[1] and serves as an enhancer of active genes[25] These findings led us to the hypothesis that TGF-β1-induced HIRA plays a role in renal fibrosis through incorporation of histone H3.3
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