The major focus of our research is to determine the molecular mechanisms underlying the accelerated development of inflammation, vascular and renal complications observed under diabetic conditions. We are examining the role of epigenetics and non-coding RNAs in the pathology of these diabetic complications, and also how persistence of epigenetic changes can create a “metabolic memory” that results in long term malfunction of genes and sustained complications even after diabetes patients bring their blood sugar under control. We use state-of-the art approaches in cell culture, animal and clinical models to examine these mechanisms leading to enhanced vascular and renal cell growth, and monocyte activation due to altered expression of inflammatory cytokines, chemokines and lipids under diabetic conditions.
We have uncovered key signaling pathways, and gene regulation mechanisms that integrate and amplify the effects of diabetogenic stimuli in target cells. Additionally, we have demonstrated the role of specific chromatin histone post-translational modifications in the epigenetic regulation of inflammatory and fibrotic genes under diabetic conditions and in the phenomenon of “metabolic memory”. We use genomic profiling approaches to map histone modifications, DNA methylation, binding of chromatin factors at diabetes-regulated genes, chromatin accessibility and transcriptome changes under diabetic conditions with techniques such as Chromatin immunoprecipitation (ChIP)-linked to Next generation sequencing (ChIP-seq), RNA-sequencing, FAIRE-sequencing and others.
Another active area is the examination of non-coding RNAs like microRNAs and and long non-coding RNAs (lncRNAs) that regulate the expression of pathological and protective genes under diabetic conditions. We discovered novel roles for certain microRNAs and lncRNAs and their downstream targets in augmenting renal fibrosis and vascular dysfunction in diabetes. We are studying microRNA knockout mice, and also the therapeutic efficacy of novel inhibitors of non-coding RNAs for diabetic kidney disease and inflammation in mouse models. Together, these approaches could lead to new therapeutic modalities for the debilitating complications of diabetes.
Partial List of Publications (selected from over 175):
Schones DA, Leung A, and Natarajan R. (2015) Chromatin modifications associated with diabetes and obesity. Atheroscler. Thromb. Vasc Biol. (In Press).
Miao F*, Chen Z*, Genuth S*, Zhang L, Wu X, Paterson AD, Lachin J, Li Sierra M, Cleary P, Riggs AD, Harlan DM, Lorenzi G, Kolterman O, Wanjie Sun, the DCCT/EDIC Research Group, and Natarajan R. (2014) Evaluating the Role of Epigenetic histone modifications in the Metabolic Memory of Type 1 Diabetes. Diabetes May;63(5):1748-62. (Commentary by L. Pirola in Same issue)Reddy MA, Chen Z, Park JT, Wang M, Lanting L, Zhang Q, Bhatt K, Leung A, Wu X, Putta S, Sætrom P and Natarajan R. (2014) Regulation of Inflammatory Phenotype in Macrophages by a Diabetes-Induced Long Noncoding RNA. Diabetes. Dec;63(12):4249-61
Kato M., and Natarajan R. (2014) Diabetic Nephropathy: Emerging Epigenetic Mechanisms. Nature Reviews Nephrology Sep;10(9):517-30.
Leung A, Parks B, Du J, Trac C, Setten R, Brown K, Lusis AJ, Natarajan R*, Schones DE,* (* Co-corresponding authors). 2014. Open chromatin profiling in mice livers reveals unique chromatin variations induced by high fat diet. J. Biol. Chem. Aug 22;289(34):23557-67. PMID:25006255[PubMed - in process] PMCID:PMC4156056[Available on 2015/8/22]
Castro NE, Kato M, Park JT and Natarajan R. (2014), Transforming growth factor β1 (TGF-β1) enhances expression of pro-fibrotic genes through a novel signaling cascade and microRNAs in renal mesangial cells. J. Biol. Chem. Oct 17;289(42):29001-13.
Reddy MA, Putta S, Lanting L, Yuan H, Wang M, Mar D, Flanagin S, Alpers C, Bomsztyk K and Natarajan R. (2013) Losartan Reverses Permissive Epigenetic Changes in Renal Glomeruli of Diabetic db/db Mice. Kidney Intl 2014 Feb;85(2):362-73 PubMed PMID: 24088954.
Kato M, Wang M, Park JT, Deshpande, Mardiros A, Dang V, Zhan Y, Oettgen P, Putta S, Lanting L, Natarajan R. (2013). TGF-β Induces Acetylation of Chromatin and of Ets-1 to Alleviate Repression of miR-192 in Diabetic Nephropathy. Science Signalling Jun 4;6(278):ra43 . (commentary in the same issue by Z. Dong)
Leung A, Trac C, Lanting L, Schones DE, and Natarajan R. (2013) Novel long non-coding RNAs are involved in cellular response to Angiotensin II-signaling. Circulation Res. 113:266-278 (Editorial Commentary by Sandberg K et al, in the same issue.
Miao F, Chen Z, Zhang L, Gao H and Natarajan R. (2013) RNA-Sequencing Analysis of High Glucose Treated Monocytes Reveals Novel Transcriptome Signatures and associated Epigenetic Profiles. Physiol Genomics. Apr 1;45(7):287-99.
Yuan H, Sun G, Lanting L, Wang M, Arce L, Kato M, Kato M and Natarajan R. (2013) Involvement of CBP/P300 and epigenetic histone acetylation in TGF-β1/Smad-pathway mediated gene transcription in mesangial cells Am. J. Physiol (Renal) 304:F601-13.
Park JT, Kato M, Yuan H, Castro N, Lanting L, Wang M and Rama Natarajan. (2013) FOG2 down-regulation by TGF-β-induced microRNA-200b/c leads to Akt kinase activation and Glomerular Mesangial Hypertrophy Related to Diabetic Nephropathy. J. Biol. Chem. 2013 Aug 2;288(31):22469-80.
Deshpande SD, Putta S, Wang M, Lai JY, Bitzer M , Nelson RG, Lanting LL, Kato M and Natarajan R. (2013) Transforming Growth Factor-β induced cross talk between p53 and a microRNA in the pathogenesis of Diabetic Nephropathy. DIABETES (In Press). 2013, 62(9):3151-62.
Putta S, Lanting L, Sun G, Lawson G, Kato M and Natarajan R . Inhibiting MicroRNA-192 Ameliorates Renal Fibrosis in Diabetic Nephropathy. (2012). J. Am. Soc. Nephrol. Mar;23(3):458-69.
Miao F, Chen Z, Zhang L, Liu Z, Wu X, Yuan Y-C and Natarajan R. (2012) Profiles of Epigenetic Histone Post-translational Modifications at Type 1 Diabetes Susceptible Genes. 2012. J. Biol. Chem . May 11;287(20):16335-45.
Jin W, Reddy MA, Chen Z, Putta S, Lanting L, Kato M, Park JT, Chandra M, Tangirala R, and Natarajan R. (2012). Small RNA Sequencing Reveals MicroRNAs That Modulate Angiotensin II Effects in Vascular Smooth Muscle Cells. J. Biol. Chem. May 4;287(19):15672-83.
Reddy MA, Wen J, Villeneuve L, Wang M, Lanting M, Todorov I, Kato M and Natarajan R. (2012). Pro-Inflammatory Role of microRNA-200 in Vascular Smooth Muscle Cells from Diabetic Mice. Arterioscler Thromb Vasc Biol Mar;32(3):721-9. Epub (2012) Jan 12. PMCID: PMC3288534.
Natarajan R, Putta S, Kato M (2012). MicroRNAs and Diabetic Complications. Special Focus Issue. Journal of Cardiovascular Translational Research Aug;5(4):413-22. PMCID:PMC3396726.
Kato M, Arce L, Wang M, Putta S, Lanting L, and Natarajan R. (2011) A microRNA circuit mediates transforming growth factor-β1 autoregulation in renal glomerular mesangial cells. Kidney International 2011 Aug;80(4):358-68 (Comment in the same issue of Kid Intl pg 334-337).
Jin F, Li Y, Ren B, Natarajan R. (2011) PU.1 and C/EBPa synergistically program distinct response to NF-κB activation through establishing monocyte-specific enhancers. Proc. Natl Acad. Sci USA. 108 (13): 5290-5295. PMID: 21402921; PubMed Central PMCID: PMC3069155.
Meng L*, Park J*, Cai Q*, Lanting L, Reddy MA and Natarajan R. (2010) Diabetic Conditions Promote Binding of Monocytes to Vascular Smooth Muscle Cells and their Subsequent Differentiation. Am. J. Physiol. Heart Circ Physiol. 298(3):H736-45. (*equal contribution) (Editorial in same issue, H731).
Villeneuve LM, Kato M, Wang M, Reddy MA, Lanting L, Natarajan R. (2010). Enhanced microRNAs-125b levels in vascular smooth muscle cells of diabetic mice leads to increased inflammatory gene expression by targeting the histone methyltransferase Suv39h1. Diabetes. 59(11):2904-15.
Villenueve LM and Natarajan R. (2010) The Role of Epigenetics in the Pathology of Diabetic Complications. American Journal of Physiology, Renal. 299: F14–F25.
Kato M, Wang L, Putta S, Wang M, Yuan H, Sun G, Lanting L, Todorov I, Rossi JJ, and Natarajan R. (2010). Post-transcriptional upregulation of Tsc-22 by Ybx1, a target of miR-216a, mediates TGF-β –induced collagen expression in renal cells. J.Biol.Chem. 285(44):34004-15. Paper of the Week - top 1% of papers.
Sun G, Reddy MA, Yuan H, Lanting L, Kato M, and Natarajan R. (2010). Epigenetic histone methylation modulates fibrotic gene expression in mesangial cells.J. Am. Soc. Nephrol. 21(12):2069-80 (PMCID: 3014020).
Kato M, Wang M, Yuan H, Lanting L, Putta P, Gunn A, Nakagawa Y, Shimano H, Rossi JJ and Natarajan R. (2009) TGF-beta activates Akt kinase via a microRNA-dependent amplifying circuit argeting PTEN. Nature Cell Biology 11:881-889. (Faculty of 1000).
Villeneuve LM, Reddy MA, Lanting L, Wang M, Meng L, Natarajan R. (2008) Epigenetic Histone H3 Lysine 9 Methylation in Metabolic Memory and Inflammatory Phenotype of Vascular Smooth Muscle Cells in Diabetes. Proc. Natl Acad Sci USA 105(26):9047-52.
Yuan H, Lanting L, Xu ZG, Wang M, Li SL, Swiderski P, Putta S, Jonnalagadda M, , Kato M and Natarajan R. (2008) Effects of Cholesterol tagged short interfering RNAs targeting 12/15-lipoxygenase on parameters of diabetic nephropathy in a mouse model of type 1 diabetes. Am. J. Physiol. (Renal) 295(2):F605-F617.
Li Y, Reddy MA, Miao F, Shanmugam N, Yee JK, Hawkins D, Ren B, Natarajan R. (2008) Role of the histone lysine methyltransferase SET7/9 in the regulation of NF-kB-dependent inflammatory genes. J. Biol. Chem. 283:26771-26781.
Miao F, David D. Smith†, Lingxiao Zhang*, Andrew Min*, Wei Feng*, Natarajan R. (2008) Lymphocytes from Patients with Type 1 diabetes Reveal a Distinct Profile of Chromatin Histone H3 Lysine 9 Dimethylation: An Epigenetic Study in Diabetes. Diabetes. 57:3189-3198. Commentary in the same issue on page 3184 by Litherland SA.
Shanmugam N, Reddy MA, Natarajan R. (2008) Distinct Roles of hnRNPK and microRNA-16 in S100b Induced Cyclooxygenase-2 mRNA Stability in Monocytes. J. Biol.Chem, 283(52):36221-33. Paper of the Week. Comment in the same issue.
Kato M, Zhang J, Wang M, Yuan H, Rossi JJ, Natarajan R. (2007) MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors. Proc. Natl. Acad. Sci. USA. 104:3432-3437.
Miao F, Wu X, Zhang L, Yuan Y-C, Riggs A, Natarajan R. (2007) Genome-wide Analysis of Histone Lysine Methylation variations under diabetic conditions in human monocytes. J. Biol. Chem. 282:13854-13863.
Guha M, Xu ZG, Tung D, Lanting L, Natarajan R. (2007) . Antisense Oligonucleotide to Connective Tissue Growth Factor attenuates Progression of Nephropathy in Mouse Models of Type 1 and Type 2 Diabetes. FASEB J. 21(12):3355-68.