Histone modifications in kidney disease Masaomi Nangaku Division of Nephrology and Endocrinology The University of Tokyo Graduate School of Medicine Japan
Mimura, Tanaka, & Nangaku. Semin Nephrol 2013
Mimura, Tanaka, & Nangaku. Semin Nephrol 2013
Legacy effect: UKPDS Holman et al. N Engl J Med 2008
Histone modification
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
Decreased H3K9me3 levels at inflammatory genes in cultured db/db VSMC H3K9me3: suppressive mark Villeneuve et al. Proc Natl Acad Sci 2008
Increased H3K9/14Ac at the PAI-1 and p21 promoters in glomeruli from diabetic mice Yuan et al. Am J Physiol Renal Physiol 2013
TGF-β1 decreases H3K9me2/3 at fibrogenic gene promoters in mesangial cells H3K9me2 H3K9me3 Sun et al. J Am Soc Nephrol 2010
A decrease in H3K27me3 in the diabetic kidney MCP-1 vimentin laminin γ1 Komers et al. Lab Invest 2013
An increase in KDM6A in the diabetic kidney KDM6A: H3K27me3 demethylase Komers et al. Lab Invest 2013
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
Mimura, Tanaka, & Nangaku. Semin Nephrol 2013
AKI: No CKD Progression GFR AKI: CKD Progression AKI on CKD: CKD Progression
Why does AKI progress to CKD? Chawla & Kimmel. Kidney Int 2012
G2/M arrest mediates fibrosis after AKI G2/M arrest JNK c-jun fibrosis Yang et al. Nature Med 2010
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
Effect of gender on ischemiainduced kidney injury Park et al. J Biol Chem 2004
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
Hypoxia inducible factor (HIF)
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 TM6089 200 180 160 140 120 100 Validation of 80 60 Clinical benefits 40 (e.g.,sponge assays 20 of angiogenesis) 0 vehicle TM6008 Nangaku, Miyata et al. Arterio Throm Vas Biol 2007
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
Histone demethylation by hypoxia 1400 1400 1200 1200 1000 1000 800 800 600 600 400 200 0 0 Upregulation of KDM3A h hr hrs hrs 8 hrs 12hrs 24hrs 0 1 2 4 8 24 hr KDM3A = Jmjd1a demethylase of H3K9me2 OFF ON supprssive H3K9me2 Mimura, Nangaku et al. Mol Cell Biol 2012
Histone demethylation by hypoxia 1400 1400 1200 1200 1000 1000 800 800 600 600 400 200 0 0 Upregulation of KDM3A h hr hrs hrs 8 hrs 12hrs 24hrs 0 1 2 4 8 24 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
Regulation of GLUT3 expression by hypoxia normoxia hypoxia GLUT3 GLUT3 Up-regulation Mimura, Nangaku et al. Mol Cell Biol 2012
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
HIF-1 mediates recruitment of KDM4C (JMJD2C) to HIF-1 target genes Luo et al. PNAS 2012
I/R and LPS increased histone acetylation of TNF-α synergistically Bomsztyk et al. PLoS One 2013
Marked up-regulation of angiopoietin-like protein 4 in renal hypoxia Kojima, Nangaku et al. Kidney Int 2009
Cross-enhancement of ANGPTL4 transcription by HIF1 and PPAR β/δ HIF1α PPARβ/δ Inoue, Nangaku et al. Genome Biol 2014
ChIP-PCR of H3K27ac around the PPARβ/δ binding site around the HIF1 binding site Inoue, Nangaku et al. Genome Biol 2014
The chromatin conformational change at the ANGPTL4 locus by HIF1α and PPARβ/δ Inoue, Nangaku et al. Genome Biol 2014
Inoue, Nangaku et al. Genome Biol 2014
Mimura, Tanaka & Nangaku. Semin Nephrol 2013
epigenetic therapy Treppendahl et al. J Clin Invest 2014
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.
Tatsuhiko Hiroyuki Takshi Toshio Masayuki Kai-Uwe Kodama Aburatani Kadowaki Miyata Yamamoto Eckardt