Why should we consider epigenetics in metabolic disorders?
Complex metabolic disorders including obesity and type 2 diabetes result from intricate interactions between internal genetic makeup and external environment, which is mediated by epigenetic mechanisms. There are compelling reasons to think epigenetic control may have a direct role in the pathogenesis of metabolic dysregulation; 1) Genetic differences can not fully explain many etiological features of metabolic disorders, such as high heritability, high discordance of metabolic disorders in adult monozygotic twins, and the close relationship with lifestyle factors. Therefore, other forms of non-genetic variation, such as epigenetic alterations, should be considered in the etiology. 2) Drugs that affect chromatin remodeling, such as the HDAC inhibitors are known to affect insulin sensitivity in cells, animal models, and human subjects. 3) Collective studies report global and locus-specific epigenetic changes at key metabolic genes often accompanying reduced gene expression in association with various metabolic perturbations. 4) Most convincingly, studies have shown that several mouse genetic models carrying mutations in genes encoding epigenetic modifiers display marked metabolic phenotypes. Despite these notions, the accurate role for the epigenetic modifiers in metabolic regulation largely remains unknown.
Epigenomic profiling is a powerful discovery tool.
Insulin resistance is a sine qua non of type 2 diabetes and is associated with many other clinical conditions including obesity, cardiovascular diseases, and cancer. As an effort to identify novel transcriptional pathways of insulin resistance, we constructed global transcriptional and H3K27ac enhancer maps of insulin resistance using comparative models of insulin resistance induced by dexamethasone (Dex) or tumor necrosis factor-a (TNF) in cultured adipocytes. As a result, we detected several locus-specific H3K27ac positive enhancers that display coordinate regulation nearby the co-induced genes by Dex and TNF. Motif analysis on these enhancer regions led us to discover transcriptional pathways insulin resistance, from which I demonstrated the biological significance of the glucocorticoid receptor (GR) and vitamin D receptor (VDR) as common nodes for Dex and TNF mediated insulin resistance. Further, through integrative analysis of our epigenomic and transcriptomic data, we unraveled a core target genes of GR and VDR that can be used as molecular signature of insulin resistance. These studies illustrate the power of epigenomic profiling as a tool for the identification of novel pathogenic disease mechanisms.
Our research mission
Our research goal is to gain more accurate understanding of how epigenetic and transcriptional regulators control (patho)physiology of adipose and other metabolic tissues. Ultimately, we hope to identify novel drug targets for more safe and efficient therapeutic intervention to relevant metabolic disorders including obesity and type 2 diabetes. The key questions that we address are; 1) What are the core epigenetic events underlying obesity and insulin resistance, especially in the fat tissue? 2) Does the adverse epigenetic have a direct contribution to the pathogenesis?, 3) If so, how does so?, and, 4) Can we fix the adverse epigenetic events to mitigate the condition?
To answer these questions, we are uniquely geared to integrate a wide variety of approaches, from highly mechanistic studies in vitro and in vivo, metabolic characterization of genetically modified mouse models, and to global profiling studies such ahs ChIP-Seq and RNA-Seq.
- Ph.D University of Michigan, Molecular and Integrative Physiology Post-doctoral fellow/Instructor Beth Israel Deaconess Medical Center/Harvard Medical School, Endocrinology
1. Kang BY, Chung SW, Kim SH, Kang SN, Choe YK, Kim TS. Retinoid-mediated inhibition of interleukin-12 production in mouse macrophages suppresses Th1 cytokine profile in CD4 (+) T cells. Br J Pharmacol. 130,3, 581-6, 2000
2. Kim TS, Chung SW, Kim SH, Kang SN, Kang BY. Therapeutic anti-tumor response induced with epitope-pulsed fibroblasts genetically engineered for B7.1 expression and IFN-gamma secretion. Int J Cancer. 87, 3, 427-33, 2000
3. Kang SN, Lee MH, Kim KM, Cho D, Kim TS. Induction of human promyelocytic leukemia HL-60 cell differentiation into monocytes by silibinin: involvement of protein kinase C. Biochem Pharmacol. 61, 12, 1487-95, 2001
4. Kang SN, Chung SW, Kim TS. Capsaicin potentiates 1,25-dihydoxyvitamin D3- and all-trans retinoic acid-induced differentiation of human promyelocytic leukemia HL-60 cells. Eur J Pharmacol. 420, 2-3, 83-90, 2001
5. Kang SN, Kim SH, Chung SW, Lee MH, Kim HJ, Kim TS. Enhancement of 1 alpha,25-dihydroxyvitamin D(3)-induced differentiation of human leukemia HL-60 cells into monocytes by parthenolide via inhibition of NF-kappa B activity. Br J Pharmacol. 135, 5, 1235-44, 2002
6. Kim SH, Kang SN, Kim HJ, Kim TS. Potentiation of 1, 25-dihydroxyvitamin D(3)-induced differentiation of human promyelocytic leukemia cells into monocytes by costunolide, a germacranolide sesquiterpene lactone. Biochem Pharmacol. 64, 8, 1233-42, 2002
7. Longo KA, Wright WS, Kang S, Gerin I, Chiang SH, Lucas PC, Opp MR, MacDougald OA. Wnt10b inhibits development of white and brown adipose tissues. J Biol Chem. 279, 34, 35503-9, 2004
8. Kang S, Bajnok L, Longo KA, Petersen K, Hansen JB, Kristiansen K, MacDougald OA. Effects of Wnt signaling on brown adipocyte differentiation and metabolism mediated by PGC-1a. Mol Cell Biol. 25, 4, 1272-82, 2005
9. Hall CL, Kang S, MacDougald OA, Keller ET. "The Role of Wnts in prostate cancer bone metastases" J Cell Biochem. 97, 4, 661-72, 2006
10. Kang S, Dolinsky VW, and MacDouglad OA. Energy balance in simple organisms: Will fatty worms, flies or fish help cure human obesity? In: Genetics of Obesity. Ed. K. Clement and T. Sorensen. Book Chapter, 2006
11. Wright WS, Longo KA, Dolinsky VW, Gerin I, Kang S, Bennett CN, Chiang CH, Prestwich TC, Gress C, Burant CF, Susulic VS, MacDougald OA. Wnt10b inhibits obesity in Ob/Ob and agouti mice. Diabetes. 56, 295-303, 2007
12. Kang S, Bennett CN, Gerin I, Rapp LA, Hankenson K, and MacDougald OA. Wnt signaling regulates mesenchymal cell fate between by suppressing C/EBPa and PPARg. J Biol Chem. 282, 14515-24, 2007
13. Kang S, Dolinsky V, and MacDougald OA. Will Fatty Worms or Flies Help Discover the Mechanism of Human Obesity? Obesity Genomics and Post Genomics, Book Chapter, 2007.
14. Cha B, Sharma N, Kang S, Prestwich S, Gerin I, and MacDougald OA. The effect of phosphorylation of C/EBPa in development and metabolism of adipose tissue. J Biol Chem. 283, 18002-11, 2008
15. Waki H, Park KW, Kang S, MacDougald OA, and Tontonoz P. Inhibitor of DNA binding 2 is a small molecule-inducible modulator of peroxisome proliferator-activated receptor-gamma expression and adipocyte differentiation. Mol Endocrinology. 22, 2038-48, 2008
16. Bock J, Fukuyoa Y, Kang S, Phipps ML, Alexandrova LB, Rasmussen K, Bishop AR, Rosen ED, Martinez JS, Chen H, Rodriguez G, Alexandrov BS and Usheva A. Mammalian stem cells respond to terahertz radiation with changes in gene expression. PloS One. 12, e15806-15812, 2010
17. Kang S, Akerblad P, Kiviranta R, Gupta R, Kajimura S, Baron R, Rosen ED. Regulation of early adipose commitment by Zfp521. PloS Biology. 11, 1001433- 001442, 2012
18. Eguchi J, Kong X, Tenta M, Wang X, Kang S, and Rosen ED. Interferon regulatory factor 4 regulates obesity-induced inflammation through regulation of adipose tissue macrophage polarization. Diabetes. 62, 10, 3394-3403, 2013
19. Griffin MJ, Zhou Y, Kang S, Zhang X, Mikkelsen TS, Rosen ED. Early B-cell Factor-1 (Ebf1) is a key regulator of metabolic and inflammatory signaling pathways in mature adipocytes. J Biol Chem, 288, 5925-5939 2013
20. Kang S, Kong X, and Rosen ED. Adipocyte-Specific Transgenic and Knockout Models. Methods in Enzymology. 537, 1-16, 2014
21. Fujikawa T, Koulova A, Lange M, Kang S, Elmadhun NY, Lassaletta AD, Bianchi C, Griffin MJ, Sellke FK, and Usheva A. Arterial-territory specific cell cycle regulation promotes differences in the vascular smooth muscle cell response to mitogenic stimuli. Cell Cycle. 15, 315-323, 2014
22. Kong X, Banks A, Liu T, Rao R, Cohen P, Wang X, Yu X, Lo J, Tseng YH, Cypess A, Xue R, Kleiner S, Kang S, Spiegelman BM and Rosen ED. IRF4 is a thermogenic transcriptional partner of PGC-1a. Cell. 158, 69-83, 2014
23. Kang S, Tsai L, Zhou Y, Evertts A, Xu S, Garcia B, Epstein CB, Mikkelsen TS, Rosen ED. Epigenomic and transcriptional analysis identifies two nuclear pathways of insulin resistance. Nat Cell Biol. 17, 44-56, October, 2015.
24. Kang S, Tsai L, Rosen ED. Nuclear mechanisms of insulin resistance. Trends in Cell Biol, 26(5):341-345, January, 2016
25. Sun X, Lin J, Zhang Y, Kang S, Belkin N, Wara AK, Icli B, Hamburg NM, Li D, Feinberg MW. MicroRNA-181b Improves Glucose Homeostasis and Insulin Sensitivity by Regulating Endothelial Function in White Adipose Tissue. Circulation. 118(5):810-821, 2016
26. Kumari M, Wang X, Lantier L, Lyubetskaya A, Eguchi J, Kang S, Tenen D, Roh HC, Kong X, Kazak L, Ahmad R, Rosen ED. IRF3 promotes adipose inflammation and insulin resistance and represses browning. J Clin Invest. 2016 Aug 1;126(8):2839-54, 2016
27. Lamichhane R, Kim SG, Kang S, Lee KH, Pandeya PR, Jung HJ. Exploration of Underlying Mechanism of Anti-adipogenic Activity of Sulfuretin. Biol Pharm Bull. 2017 Sep 1;40(9):1366-1373, 2017
28. You D, Nilsson E, Tenen DE, Lyubetskaya A, Lo JC, Jiang R, Deng J, Dawes BA, Vaag A, Ling C, Rosen ED, Kang S. Dnmt3a is an epigenetic mediator of adipose insulin resistance. eLIFE.: e30766. doi: 10.7554/eLife.30766, December, 2017
29. Bian F, Xiang M, Villivalam SD, Choy LR, Paladugu A, Fung S, and Kang S. TET2 facilitates PPARγ agonist–mediated gene regulation and insulin sensitization in adipocytes. Metabolism, Sep 5. pii: S0026-0495(18)30174-4, 2018
30. Villivalam SD, Kim JS, and Kang S. Dnmt3a and Tet2 in adipocyte insulin sensitivity. Oncotarget, Oct 11, Vol 82, 2018.
31. Xiang M, Kang S. Functional role of DNA methylation in adipose biology. Diabetes, May;68(5):871-878. doi: 10.2337/dbi18-0057. 2019.
32. Xiao H, Kang S. The role of DNA methylation in thermogenic adipose biology. Epigenetics. Jun 4:1-7. doi: 10.1080/15592294.2019.1625670. 2019.
33. Xiao H, Kang S. The role of the gut microbiome in energy balance. Frontiers Genetics. Apr 7;11:297. doi: 10.3389/fgene.2020.00297. 2020.
34. Villivalam SD, You D, Kim J, Lim HW, Xiao H, Zushin PH, Oguri Y, Amin P, Kang S. TET1 is a beige adipocyte–selective epigenetic suppressor of thermogenesis. Nat Commun. 2020 Aug 27;11(1):4313. doi: 10.1038/s41467-020-18054-y.
35. Lontchi-Yimagou E, Kang S, Goyal A, Zhang K, You JY, Carey M, Jain S, Bhansali S, Kehlenbrink S, Guo. Insulin-sensitizing effects of vitamin D repletion mediated by adipocyte vitamin D receptor. Studies in human and mice. Mol Metab. 2020 Dec;42:101095. doi: 10.1016/j.molmet.2020.101095. Epub 2020 Oct 10.
36. Kang S. Adipose tissue malfunction drives metabolic dysfunction in Alström syndrome. Diabetes, 2021 Feb;70(2):323-325. doi: 10.2337/dbi20-0041.
37. Villivalam SD, Ebert SM, Lim HW, Kim J, You D, Chung BC, Palacios HH, Adams CM, Kang S. A necessary role of DNMT3A in endurance exercise by suppressing ALDH1L1-mediated oxidative stress. EMBO, 2021 May 3;40(9):e106491. doi: 10.15252/embj.2020106491.
38. Chen T, Kuo T, Dandan M, Lee RA, Chang M, Villivalam SD, Liao S, Costello D, Shankaran M, Mohammed H, Kang S, Hellerstein MK, Wang CJ. The Role of Striated Muscle Pik3r1 in Chronic Glucocorticoid Exposure Induced Insulin Resistance, Reduced Protein Synthesis and Muscle Atrophy, J Biol Chem, 2021 Feb 7;100395.doi: 10.1016/j.jbc.2021.100395
39. Jung B, Kang, S. Epigenetic regulation of inflammatory factors in adipose tissue. Biochim Biophy Acta Mol Cell Biol Lipids. 2021 Nov;1866(11):159019. doi: 10.1016/j.bbalip.2021.159019.