Histone modifications in kidney disease
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1 Histone modifications in kidney disease Masaomi Nangaku Division of Nephrology and Endocrinology The University of Tokyo Graduate School of Medicine Japan
2 Mimura, Tanaka, & Nangaku. Semin Nephrol 2013
3 Mimura, Tanaka, & Nangaku. Semin Nephrol 2013
4 Legacy effect: UKPDS Holman et al. N Engl J Med 2008
5 Histone modification
6 Transient high glucose causes recruitment of Set7 and increased H3K4 methylation of NF-κB subunit p65 in aortic endothelial cells Set7: H3K4-specific methyltransferase H3K4me1: active enhancer mark El-Osta et al. J Exp Med 2008
7 Decreased H3K9me3 levels at inflammatory genes in cultured db/db VSMC H3K9me3: suppressive mark Villeneuve et al. Proc Natl Acad Sci 2008
8 Increased H3K9/14Ac at the PAI-1 and p21 promoters in glomeruli from diabetic mice Yuan et al. Am J Physiol Renal Physiol 2013
9 TGF-β1 decreases H3K9me2/3 at fibrogenic gene promoters in mesangial cells H3K9me2 H3K9me3 Sun et al. J Am Soc Nephrol 2010
10 A decrease in H3K27me3 in the diabetic kidney MCP-1 vimentin laminin γ1 Komers et al. Lab Invest 2013
11 An increase in KDM6A in the diabetic kidney KDM6A: H3K27me3 demethylase Komers et al. Lab Invest 2013
12 Increased transcription-permissive histone modifications and their reversal by ARB at the PAI-1 and RAGE loci in db/db mice Reddy et al. Kidney Int 2014
13 Mimura, Tanaka, & Nangaku. Semin Nephrol 2013
14 AKI: No CKD Progression GFR AKI: CKD Progression AKI on CKD: CKD Progression
15 Why does AKI progress to CKD? Chawla & Kimmel. Kidney Int 2012
16 G2/M arrest mediates fibrosis after AKI G2/M arrest JNK c-jun fibrosis Yang et al. Nature Med 2010
17 Increases in active histone marks at the collagen III gene following ischemia H3K4me3 active mark H2A.Z Zager & Johnson. Am J Physiol Renal Physiol 2009
18 Effect of gender on ischemiainduced kidney injury Park et al. J Biol Chem 2004
19 male hormones decrease expression and binding of HDAC11, resulting in an increase in PAI-1 expression in I/R injury Kim et al. Am J Physiol Renal Physiol 2013
20 Hypoxia inducible factor (HIF)
21 Novel HIF activating compound Virtual chemical library (~200 million) X-ray crystal structure of human PHD2 Virtual in silico screening (SBDD) 60 compounds Biological assay (HRE reporter) Hemoglobin Content vehicle Hit compounds TM6008 TM6008 TM Validation of Clinical benefits 40 (e.g.,sponge assays 20 of angiogenesis) 0 vehicle TM6008 Nangaku, Miyata et al. Arterio Throm Vas Biol 2007
22 Epigenetic modification of GLUT3 expression by hypoxia enhancer mark H3K4me1 normoxia H3K4me1 hypoxia H3K27ac normoxia H3K27ac hypoxia active mark H3K4me3 normoxia H3K4me3 hypoxia HIF1α normoxia HIF1α hypoxia GLUT3-24kb -35kb Mimura, Nangaku et al. Mol Cell Biol 2012
23 Histone demethylation by hypoxia Upregulation of KDM3A h hr hrs hrs 8 hrs 12hrs 24hrs hr KDM3A = Jmjd1a demethylase of H3K9me2 OFF ON supprssive H3K9me2 Mimura, Nangaku et al. Mol Cell Biol 2012
24 Histone demethylation by hypoxia Upregulation of KDM3A h hr hrs hrs 8 hrs 12hrs 24hrs hr Binding of KDM3A to GLUT3 gene Control (normoxia) Control (hypoxia) HIF1 sirna (hypoxia) TSS -35kb -24kb +91kb demethylation of suppressive H3K9me2 normoxia hypoxia normoxia hypoxia normoxia hypoxia
25 Regulation of GLUT3 expression by hypoxia normoxia hypoxia GLUT3 GLUT3 Up-regulation Mimura, Nangaku et al. Mol Cell Biol 2012
26 KDM4C (JMJD2C) is an HIF-1αinteracting protein screening for HIF-interacting proteins using GST fusion proteins containing the TAD of HIF as bait in a stable isotope labeling by amino acids in cell culture (SILAC) proteomic assay Luo et al. PNAS 2012
27 HIF-1 mediates recruitment of KDM4C (JMJD2C) to HIF-1 target genes Luo et al. PNAS 2012
28 I/R and LPS increased histone acetylation of TNF-α synergistically Bomsztyk et al. PLoS One 2013
29 Marked up-regulation of angiopoietin-like protein 4 in renal hypoxia Kojima, Nangaku et al. Kidney Int 2009
30 Cross-enhancement of ANGPTL4 transcription by HIF1 and PPAR β/δ HIF1α PPARβ/δ Inoue, Nangaku et al. Genome Biol 2014
31 ChIP-PCR of H3K27ac around the PPARβ/δ binding site around the HIF1 binding site Inoue, Nangaku et al. Genome Biol 2014
32 The chromatin conformational change at the ANGPTL4 locus by HIF1α and PPARβ/δ Inoue, Nangaku et al. Genome Biol 2014
33 Inoue, Nangaku et al. Genome Biol 2014
34 Mimura, Tanaka & Nangaku. Semin Nephrol 2013
35 epigenetic therapy Treppendahl et al. J Clin Invest 2014
36 The way to modify histone modifications of specific target genes is not established. Responses may take relatively long time after the initiation of treatment to occur.
37 Tatsuhiko Hiroyuki Takshi Toshio Masayuki Kai-Uwe Kodama Aburatani Kadowaki Miyata Yamamoto Eckardt
38
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