Role of Epigenetic Histone Modifications in Diabetic Kidney Disease Involving Renal Fibrosis

Figure 2

Histone modifications regulate gene transcription involving renal fibrosis of diabetic kidney disease. TGF-β signaling pathway, activated by high glucose, will stimulate two types of epigenetic histone mechanisms including histone acetylation and histone methylation. TGF-β1 activates the histone acetyltransferase (HAT) p300/CBP, followed by the enrichment of H3K9/14Ac and HAT p300/CBP at the promoters of renal fibrotic genes, and then increases the transcriptions of fibrotic genes and EMT progress. After induced by TGF-β1, the methyltransferase SET7/9 enriches at fibrotic gene promoters, leading to increases of positive chromatin marks, such as H3K4me1, H3K4me2, and H3K4me3, and reductions of inhibitive marks including H3K9me2 and H3K9me3, at promoters of fibrotic genes. Eventually, the expressions of renal fibrotic genes are upregulated, which will result in the progression of DKD. Another pathway, myocardin-related transcription factor A (MRTF-A), also can be activated by high glucose. MRTF-A can regulate the histone acetylation and histone methylation of renal fibrotic genes by accelerating the recruitment of HAT p300/CBP and HMT WDR5 to fibrotic gene promoters, resulting in transcriptional activation. DKD, diabetic kidney disease; TGF-β, transforming growth factor β; MRTF-A, myocardin-related transcription factor A; HAT, histone acetyltransferase; HDAC, histone deacetylase; HMT, histone methyltransferase; Smad, mothers against decapentaplegic homologue; ECM, excess extracellular matrix; EMT, epithelial-to-mesenchymal transition.