AG Epigenetics and Metabolism

Kirchner lab

Our group studies the role of epigenetics alterations in the development of obesity and type 2 diabetes. Epigenetic marks regulate gene expression by linking a person’s individual genetic makeup with the environmental exposure. Epigenetic gene regulation thus plays a key role in the etiology of many diseases including metabolic diseases such as obesity and type 2 diabetes.

We are especially interested in the dynamic regulation of DNA methylation and non-coding RNAs. Our overall aim is to understand why epigenetic marks become dysregulated in obese and diabetic subjects and to find ways to revert these marks to the healthy state. We study epigenetic marks on a genome-wide and locus-specific level using whole-genome bisulfite sequencing, RNA-sequencing, micro-arrays, pyrosequencing and many more.

Time-resolved induction and reversal of epigenetically controlled insulin resistance

Using established mouse models of insulin resistance and non-alcoholic fatty liver disease we study the precise mechanisms that leads to a shift in DNA methylation and micro-RNA expression. Due to the longitudinal study design we are able to differentiate between disease- inducing and consequential epigenetic alterations. Moreover, we apply intervention strategies that are used in subjects with metabolic diseases such as pharmacological and surgical treatments to reverse the epigenetic shifts and restore glucose and energy homeostasis.

Deciphering the epigenetic marks that lead to hepatic insulin resistance and fatty liver disease

An ongoing goal is to understand the epigenetic modifications that are associated with fatty liver and hepatic insulin resistance in obese subjects. We identified a complex network of a genetic variant, DNA methylation and the microRNA let-7e that co-regulates the expression of the gene for the insulin receptor substrate 2 IRS2. Currently we are working on potential therapies to increase IRS2 expression by restoration of the epigenetic marks.

Selected Publications

Oelkrug R, Krause C, Herrmann B, Resch J, Gachkar S, El Gammal AT, Wolter S, Mann O, Oster H, Kirchner H, Mittag J. Maternal Brown Fat Thermogenesis Programs Glucose Tolerance in the Male Offspring. Cell Rep. 2020 Nov 3;33(5):108351. doi: 10.1016/j.celrep.2020.108351.

Krause C, Schaake S, Grütz K, Sievert H, Reyes CJ, König I, Laabs BJ, Jamora RD, Rosales RL, Diesta CCE, Pozojevic J, Gemoll T, Westenberger A, Kaiser, FJ, Klein C, Kirchner H. “DNA Methylation as a Potential Molecular Mechanism in X-Linked Dystonia-Parkinsonism”. Mov Disord. 2020 Dec;35(12):2220-2229. doi: 10.1002/mds.28239.

Krause C., C. Geissler, H. Tackenberg , A. T. El-Gammal, S. Wolter, J. Spranger, O. Mann, H. Lehnert, and H. Kirchner. „Multi-layered epigenetic regulation of IRS2 expression in the liver of obese individuals with type 2 diabetes.” Diabetologia. 2020 Oct;63(10):2182-2193. doi: 10.1007/s00125-020-05212-6.

Krause C, Sievert H, Geissler C, Grohs M, El Gammal AT, Wolter S, Ohlei O, Kilpert F, Kramer UM, Kasten M, Klein C, Brabant GE, Mann O, Lehnert H, Kirchner H (2019) Critical evaluation of the DNA-methylation markers ABCG1 and SREBF1 for Type 2 diabetes stratification. Epigenomics 11: 885-897. doi: 10.2217/epi-2018-0159

Oelkrug R, Herrmann B, Geissler C, Harder L, Koch C, Lehnert H, Oster H, Kirchner H, Mittag J. Dwarfism and insulin resistance in male offspring caused by α1-adrenergic antagonism during pregnancy. Mol Metab. 2017 Oct;6(10):1126-1136. doi: 10.1016/j.molmet.2017.06.016. Epub 2017 Jul 1. PMID: 29031714

Kirchner H, Sinha I, Gao H, Ruby MA, Schönke M, Lindvall JM, Barrès R, Krook A, Näslund E, Dahlman-Wright K, Zierath JR. Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patients. Mol Metab. 2016 Jan 2;5(3):171-83. doi: 10.1016/j.molmet.2015.12.004. eCollection 2016 Mar. PubMed PMID: 26977391; PubMed Central PMCID: PMC4770265.

Multhaup ML, Seldin MM, Jaffe AE, Lei X, Kirchner H, Mondal P, Li Y, Rodriguez V, Drong A, Hussain M, Lindgren C, McCarthy M, Näslund E, Zierath JR, Wong GW, Feinberg AP. Mouse-human experimental epigenetic analysis unmasks dietary targets and genetic liability for diabetic phenotypes. Cell Metab. 2015 Jan 6;21(1):138-49. doi: 10.1016/j.cmet.2014.12.014. PubMed PMID: 25565211; PubMed Central PMCID: PMC4340475.

Kirchner H, Nylen C, Laber S, Barrès R, Yan J, Krook A, Zierath JR, Näslund E. Altered promoter methylation of PDK4, IL1 B, IL6, and TNF after Roux-en Y gastric bypass. Surg Obes Relat Dis. 2014 Jul-Aug;10(4):671-8. doi: 10.1016/j.soard.2013.12.019. Epub 2014 Jan 28.

Finan B, Ma T, Ottaway N, Müller TD, Habegger KM, Heppner KM, Kirchner H, Holland J, Hembree J, Raver C, Lockie SH, Smiley DL, Gelfanov V, Yang B, Hofmann S, Bruemmer D, Drucker DJ, Pfluger PT, Perez-Tilve D, Gidda J, Vignati L, Zhang L, Hauptman JB, Lau M, Brecheisen M, Uhles S, Riboulet W, Hainaut E, Sebokova E, Conde-Knape K, Konkar A, DiMarchi RD, Tschöp MH. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci Transl Med. 2013 Oct 30;5(209):209ra151. doi: 10.1126/scitranslmed.3007218. PubMed PMID: 24174327.

Habegger KM, Kirchner H, Yi CX, Heppner KM, Sweeney D, Ottaway N, Holland J, Amburgy S, Raver C, Krishna R, Müller TD, Perez-Tilve D, Pfluger PT, Obici S, DiMarchi RD, D'Alessio DA, Seeley RJ, Tschöp MH. GLP-1R agonism enhances adjustable gastric banding in diet-induced obese rats. Diabetes. 2013 Sep;62(9):3261-7. doi: 10.2337/db13-0117. Epub 2013 Jun 17. PubMed PMID: 23775764; PubMed Central PMCID: PMC3749327.

Barres R, Kirchner H, Rasmussen M, Yan J, Kantor FR, Krook A, Näslund E, Zierath JR. Weight loss after gastric bypass surgery in human obesity remodels promoter methylation. Cell Rep. 2013 Apr 25;3(4):1020-7. doi: 10.1016/j.celrep.2013.03.018. Epub 2013 Apr 11.

Kirchner H, Osler ME, Krook A, Zierath JR. Epigenetic flexibility in metabolic regulation: disease cause and prevention? Trends Cell Biol. 2013 May;23(5):203-9. doi: 10.1016/j.tcb.2012.11.008. Epub 2012 Dec 29. Review. PubMed PMID: 23277089.

Chambers AP, Kirchner H, Wilson-Perez HE, Willency JA, Hale JE, Gaylinn BD, Thorner MO, Pfluger PT, Gutierrez JA, Tschöp MH, Sandoval DA, Seeley RJ. The effects of vertical sleeve gastrectomy in rodents are ghrelin independent. Gastroenterology. 2013 Jan;144(1):50-52.e5. doi: 10.1053/j.gastro.2012.09.009.Epub 2012 Sep 17. PubMed PMID: 22995675; PubMed Central PMCID: PMC3752595.

Kirchner H, Hofmann SM, Fischer-Rosinský A, Hembree J, Abplanalp W, Ottaway N, Donelan E, Krishna R, Woods SC, Müller TD, Spranger J, Perez-Tilve D, Pfluger PT, Tschöp MH, Habegger KM. Caloric restriction chronically impairs metabolic programming in mice. Diabetes. 2012 Nov;61(11):2734-42. doi: 10.2337/db11-1621. Epub 2012 Jul 10. PubMed PMID: 22787140; PubMed Central PMCID: PMC3478536.

Barnett BP, Hwang Y, Taylor MS, Kirchner H, Pfluger PT, Bernard V, Lin YY, Bowers EM, Mukherjee C, Song WJ, Longo PA, Leahy DJ, Hussain MA, Tschöp MH, Boeke JD, Cole PA. Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor. Science. 2010 Dec 17;330(6011):1689-92. doi:10.1126/science.1196154. Epub 2010 Nov 18. PubMed PMID: 21097901; PubMed Central PMCID: PMC3068526.

Day JW, Ottaway N, Patterson JT, Gelfanov V, Smiley D, Gidda J, Findeisen H, Bruemmer D, Drucker DJ, Chaudhary N, Holland J, Hembree J, Abplanalp W, Grant E, Ruehl J, Wilson H, Kirchner H, Lockie SH, Hofmann S, Woods SC, Nogueiras R,Pfluger PT, Perez-Tilve D, DiMarchi R, Tschöp MH. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat Chem Biol. 2009 Oct;5(10):749-57.doi: 10.1038/nchembio.209. Epub 2009 Jul 13. PubMed PMID: 19597507.

Kirchner H, Gutierrez JA, Solenberg PJ, Pfluger PT, Czyzyk TA, Willency JA, Schürmann A, Joost HG, Jandacek RJ, Hale JE, Heiman ML, Tschöp MH. GOAT links dietary lipids with the endocrine control of energy balance. Nat Med. 2009 Jul;15(7):741-5. doi: 10.1038/nm.1997. Epub 2009 Jun 5. Erratum in: Nat Med. 2009 Sep;15(9):1093. PubMed PMID: 19503064; PubMed Central PMCID: PMC2789701.