MAJA JAGODIC GROUP
Epigenetic origins and mechanisms in neuroinflammation
Our vision is to understand how epigenome integrates instructions from genetic and lifestyle factors and renders pathogenic immune cells ‘aggressive’ and target brain cells ‘vulnerable’ in persons affected by Multiple Sclerosis.
Our goal is to better understand disease etiology and to improve disease management through personalized treatments and more specific biomarkers.
Multiple Sclerosis (MS) is a chronic inflammatory disease characterized by autoimmune destruction of myelin and neurons in the central nervous system. Today, MS is the most common cause of non-traumatic neurological disability among young adults. Predisposition to MS, similar to other common diseases, irrefutably depends on the complex interplay between genetic and environmental factors. Nevertheless, the epigenetic mechanisms that provide a molecular link between the genome and ‘environmental’ signals and control activity of the genome are still virtually unexplored.
Epigenetic changes are heritable through cell division, controlling gene expression without altering DNA sequence (the genetic code). They provide additional and more flexible level of regulation on the top of the genetic code that can also be modulated by environment. We focus on the role of DNA methylation and non-coding RNAs (ncRNAs), especially microRNAs (miRNA).
Due to their stability, epigenetic changes may provide better etiologic clues and biomarkers. Due to their reversibility, it will become possible to alter unfavorable epigenetic states towards recovery. Therefore, characterizing epigenetic mechanisms gives tremendous opportunities and may open promising insights into pathogenesis of MS, facilitate diagnosis and improve drug development and the treatment of MS patients.
European Research Council (ERC)
Knut and Alice Wallenberg Foundation
Swedish Research Council grant
Karolinska Institutet Senior Research Fellow Grant
Karolinska Institutet KID-grants
Stockholm County Council (ALF Project)
Margaretha af Ugglas Foundation
MSIF-McDonald Fellowship Grant
Åke Wibergs Foundation
Swedish Multiple Sclerosis Research Foundation
AstraZeneca/SciLifeLab Joint Research Collaboration (co-applicant)
Swedish Research Council Young Investigator Grant
Karolinska Institutet extension of Assistant Professor Grant
Swedish Research Council Assistant Professor Grant
Karolinska Institutet KID-grants
Petrus och Augusta Hedlunds Foundation
Åke Wibergs Foundation
Swedish Society of Medicine
Epigenetic mechanisms of heritable risk factors
Epigenetic landscape of inflammatory cells
A role of micro RNAs in neuroinflammation
DNA methylation of multiple sclerosis lesions
DNA methylation of cell mediators in multiple sclerosis and animal models
Factors that control epigenetic states
Vitamin D induced epigenetic changes
Genetic control of epigenetic states
We are utilizing unique and high-quality clinical cohorts in combination with state-of-the-art methods to measure DNA methylation and transcription in discrete cell types, followed by functional studies in experimental models.
We, among other meetings, regularly attend:
International Congress of Neuroimmunology (ISNI congress)
The Wellcome Trust Epigenomics of Common Diseases conference
The European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) congress
We organize the following doctoral courses at KI:
Epigenetics and its Applications in Clinical Research (#2601)
Clinical and Experimental Neuroimmunology (#1627)
Master’s and other projects:
We are always looking for talented and interested students
Awards and Prizes
Maja Jagodic received the KI Postdoc association Best PI at KI award in December 2015.
Eliane Piket (on stage) won the best short talk prize at the Karolinska Institutet Inflammation and Immunology (KIIM) network retreat, October 2019.
Majid Pahlevan Kakhki won a poster prize of €250 at 34th Ernst Klenk Symposium in Molecular Medicine: Epigenetics: Basic principles and clinical applications, held in Cologne, Germany in October 2018.
Ewoud Ewing won a prize for a pitch presentation of his research at the MultipleMS PhD/postdoc challenge in Copenhagen, Denmark in December 2017.
Majid Pahlevan Kakhki and Eliane Piket received Best Young Investigator Poster Presentations award at the MSVirtual2020, the 8th joint ACTRIMS-ECTRIMS meeting, held 11-13 September 2020.
Maja Jagodic, Group Leader: October 1, 2019:
November 29, 2018: ERC grant
2020: EUbOPEN EU/IMI2
Lara Kular received a SEK 500 000 research grant from Petrus och Augusta Hedlunds Stiftelse in May 2020.
Ewoud Ewing was awarded 139 000 SEK from the Swedish Multiple Sclerosis research foundation (MS-forskningsfonden) in 2019.
Lara Kular (first from right) was awarded a grant of 206 800 SEK from Karolinska Institutets Funds specifically supporting young researchers in 2018.
Majid Pahlevan Kakhki was awarded the MSIF-ECTRIMS McDonald fellowship of £64 000 in 2018
Eliane Piket (first from right) was awarded 125 000 SEK from the Swedish Multiple Sclerosis research foundation (MS-forskningsfonden) in 2017.
Galina Zheleznyakova (second from right) was awarded a postdoctoral fellowship from the Swedish Society for Medical Research (SSMF) in 2016.
Lara Kular (second from right) was awarded 150 000 SEK from the Swedish Multiple Sclerosis research foundation (MS-forskningsfonden) in 2015.
News in the media
Interview with Maja Jagodic in Swedish Television for the new program Rapport, on September 3rd 2020: https://www.svt.se/nyheter/inrikes/kampen-for-forskarnas-finansiering-hardnar
Interview with Maja Jagodic, published 2020 at the Knut and Alice Wallenberg Foundation website: "Developing molecular tools to slow MS"
Knut and Alice Wallenberg Foundation, October 1 2019: Grant for the project ”Epigenomic states underlying aggressive inflammation and brain tissue loss in Multiple Sclerosis”
KI News, November 29 2018: ERC grants for research on MS, schizophrenia, and spider-silk fibers
KI News, June 19 2018: Mechanism controlling multiple sclerosis risk identified
Science daily, June 19 2018: Mechanism controlling multiple sclerosis risk identified
Multiple Sclerosis News Today, November 22, 2017: Smoking induces DNA methylation changes in multiple sclerosis patients
Multiple MS Newsletter: MultipleMS
KI Postdoc association Newsletter, December 2015: Best PI at KI award
For full list of publications, please visit Google Scholar link.
Berglund R, Guerreiro-Cacais AO, Adzemovic MZ, Zeitelhofer M, Lund H, Ewing E, Ruhrmann S, Nutma E, Parsa R, Thessen-Hedreul M, Amor S, Harris RA, Olsson T and Jagodic M. Microglial autophagy-associated phagocytosis is essential for recovery from neuroinflammation. Science Immunology, 16 October 2020, doi: 10.1126/sciimmunol.abb5077. PMID: 33067381
N'diaye M, Brauner S, Flytzani S, Kular L, Warnecke A, Adzemovic MZ, Piket E, Min JH, Edwards W, Mela F, Choi HY, Magg V, James T, Linden M, Reichardt HM, Daws MR, van Horssen J, Kockum I, Harris RA, Olsson T, Guerreiro-Cacais AO, Jagodic M. C-type lectin receptors Mcl and Mincle control development of multiple sclerosis-like neuroinflammation. J Clin Invest. 2019 Nov 14. pii: 125857. doi: 10.1172/JCI125857. [Epub ahead of print] PubMed PMID: 31725411
International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science. 2019 Sep 27;365(6460). pii: eaav7188. doi: 10.1126/science.aav7188. PubMed PMID: 31604244
Theodoropoulou E, Alfredsson L, Piehl F, Marabita F, Jagodic M. Different epigenetic clocks reflect distinct pathophysiological features of multiple sclerosis. Epigenomics. 2019 Sep;11(12):1429-1439. doi: 10.2217/epi-2019-0102. Epub 2019 Oct 8. PubMed PMID: 31592692
Ringh MV, Hagemann-Jensen M, Needhamsen M, Kular L, Breeze CE, Sjöholm LK, Slavec L, Kullberg S, Wahlström J, Grunewald J, Brynedal B, Liu Y, Almgren M, Jagodic M, Öckinger J, Ekström TJ. Tobacco smoking induces changes in true DNA methylation, hydroxymethylation and gene expression in bronchoalveolar lavage cells. EBioMedicine. 2019 Aug;46:290-304. doi: 10.1016/j.ebiom.2019.07.006. Epub 2019 Jul 12. PubMed PMID: 31303497; PubMed Central PMCID: PMC6710853
Carlström KE, Ewing E, Granqvist M, Gyllenberg A, Aeinehband S, Enoksson SL, Checa A, Badam TVS, Huang J, Gomez-Cabrero D, Gustafsson M, Al Nimer F, Wheelock CE, Kockum I, Olsson T, Jagodic M, Piehl F. Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes. Nat Commun. 2019 Jul 12;10(1):3081. doi: 10.1038/s41467-019-11139-3. PubMed PMID: 31300673; PubMed Central PMCID: PMC6626021
Kular L, Needhamsen M, Adzemovic MZ, Kramarova T, Gomez-Cabrero D, Ewing E, Piket E, Tegnér J, Beck S, Piehl F, Brundin L, Jagodic M. Neuronal methylome reveals CREB-associated neuro-axonal impairment in multiple sclerosis. Clin Epigenetics. 2019 May 30;11(1):86. doi: 10.1186/s13148-019-0678 1. PubMed PMID: 31146783; PubMed Central PMCID: PMC6543588
Ewing E, Kular L, Fernandes SJ, Karathanasis N, Lagani V, Ruhrmann S, Tsamardinos I, Tegner J, Piehl F, Gomez-Cabrero D, Jagodic M. Combining evidence from four immune cell types identifies DNA methylation patterns that implicate functionally distinct pathways during Multiple Sclerosis progression. EBioMedicine. 2019 May;43:411-423. doi: 10.1016/j.ebiom.2019.04.042. Epub 2019 Apr 30. PubMed PMID: 31053557; PubMed Central PMCID: PMC6558224
Piket E, Zheleznyakova GY, Kular L, Jagodic M. Small non-coding RNAs as important players, biomarkers and therapeutic targets in multiple sclerosis: A comprehensive overview. J Autoimmun. 2019 Jul;101:17-25. doi: 10.1016/j.jaut.2019.04.002. Epub 2019 Apr 20. Review. PubMed PMID: 31014917
Lund H, Pieber M, Parsa R, Han J, Grommisch D, Ewing E, Kular L, Needhamsen M, Espinosa A, Nilsson E, Överby AK, Butovsky O, Jagodic M, Zhang XM, Harris RA. Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells. Nat Commun. 2018 Nov 19;9(1):4845. doi: 10.1038/s41467-018-07295-7. PubMed PMID: 30451869; PubMed Central PMCID: PMC6242869
International Multiple Sclerosis Genetics Consortium. Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk. Cell. 2018 Nov 29;175(6):1679-1687.e7. doi: 10.1016/j.cell.2018.09.049. Epub 2018 Oct 18. PubMed PMID: 30343897; PubMed Central PMCID: PMC6269166
Kular L, Liu Y, Ruhrmann S, Zheleznyakova G, Marabita F, Gomez-Cabrero D, et al. DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis. Nat Commun 2018 06;9(1):2397
Lund H, Pieber M, Parsa R, Grommisch D, Ewing E, Kular L, et al. Fatal demyelinating disease is induced by monocyte-derived macrophages in the absence of TGF-β signaling. Nat. Immunol. 2018 May;19(5):1-7
James T, Lindén M, Morikawa H, Fernandes SJ, Ruhrmann S, Huss M, Brandi M, Piehl F, Jagodic M, Tegnér J, Khademi M, Olsson T, Gomez-Cabrero D, Kockum I. Impact of genetic risk loci for multiple sclerosis on expression of proximal genes in patients. Hum Mol Genet. 2018 Mar 1;27(5):912-928. doi: 10.1093/hmg/ddy001. PubMed PMID: 29325110
Marabita F, Almgren M, Sjöholm LK, Kular L, Liu Y, James T, Kiss NB, Feinberg AP, Olsson T, Kockum I, Alfredsson L, Ekström TJ, Jagodic M. Smoking induces DNA methylation changes in Multiple Sclerosis patients with exposure-response relationship. Sci Rep. 2017 Nov 6;7(1):14589. doi: 10.1038/s41598-017-14788-w. Erratum in: Sci Rep. 2018 Mar 7;8(1):4340. PubMed PMID: 29109506; PubMed Central PMCID: PMC5674007
Ruhrmann S, Ewing E, Piket E, Kular L, Cetrulo Lorenzi JC, Fernandes SJ, Morikawa H, Aeinehband S, Sayols-Baixeras S, Aslibekyan S, Absher DM, Arnett DK, Tegner J, Gomez-Cabrero D, Piehl F, Jagodic M. Hypermethylation of MIR21 in CD4+T cells from patients with relapsing-remitting multiple sclerosis associates with lower miRNA-21 levels and concomitant up-regulation of its target genes. Mult Scler. 2018 Sep;24(10):1288-1300. doi: 10.1177/1352458517721356. Epub 2017 Aug 2. PubMed PMID: 28766461; PubMed Central PMCID: PMC5794671
Zheleznyakova GY, Piket E, Marabita F, Pahlevan Kakhki M, Ewing E, Ruhrmann S, Needhamsen M, Jagodic M, Kular L. Epigenetic research in multiple sclerosis: progress, challenges, and opportunities. Physiol Genomics. 2017 Sep 1;49(9):447-461. doi: 10.1152/physiolgenomics.00060.2017. Epub 2017 Jul 28. Review. PubMed PMID: 28754822
Meng W, Zhu Z, Jiang X, Too CL, Uebe S, Jagodic M, Kockum I, Murad S, Ferrucci L, Alfredsson L, Zou H, Klareskog L, Feinberg AP, Ekström TJ, Padyukov L, Liu Y. DNA methylation mediates genotype and smoking interaction in the development of anti-citrullinated peptide antibody-positive rheumatoid arthritis. Arthritis Res Ther. 2017 Mar 29;19(1):71. doi: 10.1186/s13075-017-1276-2. PubMed PMID: 28356135; PubMed Central PMCID: PMC5372280
Zeitelhofer M, Adzemovic MZ, Gomez-Cabrero D3,4,5, Bergman P, Hochmeister S, N’diaye M, Paulson A, Ruhrmann S, Almgren M, Tegnér JN, Ekström TJ, Guerreiro-Cacais AO, Jagodic M. Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2017 Feb 28;114(9):E1678-E1687. doi: 10.1073/pnas.1615783114. Epub 2017 Feb 14. PubMed PMID: 28196884; PubMed Central PMCID: PMC5338504.
Bergman P, Piket E, Khademi M, James T, Brundin L, Olsson T, Piehl F, Jagodic M. Circulating miR-150 in CSF is a novel candidate biomarker for multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2016 Apr 20;3(3):e219. doi:10.1212/NXI.0000000000000219. eCollection 2016 Jun. PubMed PMID: 27144214; PubMed Central PMCID: PMC4841644.
Ruhrmann S, Stridh P, Kular L, Jagodic M. Genomic imprinting: A missing piece of the Multiple Sclerosis puzzle? Int J Biochem Cell Biol. 2015 Oct;67:49-57.
Guerreiro-Cacais AO, Laaksonen H, Flytzani S, N’diaye M, Olsson T, Jagodic M. Translational utility of experimental autoimmune encephalomyelitis: recent developments. J Inflamm Res. 2015 Nov 13;8:211-25.
Bäckdahl L, Ekman D, Jagodic M, Olsson T, Holmdahl R. Identification of candidate risk gene variations by whole-genome sequence analysis of four rat strains commonly used in inflammation research. BMC Genomics. 2014 May 21;15:391.
Esteki-Zadeh A, Karimi M, Strååt K, Ammerpohl O, Zeitelhofer M, Jagodic M, Mehrab-Mohseni M, Sjöholm L, Rahbar A, Söderberg-Nauclér C, Ekström TJ. Epigenetics. Human cytomegalovirus infection is sensitive to the host cell DNA methylation state and alters global DNA methylation capacity. 2012 Jun 1;7(6):585-93.
Colacios C, Casemayou A, Dejean AS, Gaits-Iacovoni F, Pedros C, Bernard I, Lagrange D, Deckert M, Lamouroux L, Jagodic M, Olsson T, Liblau RS, Fournié GJ, Saoudi A. The p.Arg63Trp polymorphism controls Vav1 functions and Foxp3 regulatory T cell development. J Exp Med. 2011 Oct 24;208(11):2183-91.
Farrar D, Rai S, Chernukhin I, Jagodic M, Ito Y, Yammine S, Ohlsson R, Murrell A, Klenova E. Mutational analysis of the poly(ADP-ribosyl)ation sites of the transcription factor CTCF provides an insight into the mechanism of its regulation by poly(ADP-ribosyl)ation. Mol Cell Biol. 2010 Mar;30(5):1199-216.
Piehl F, Jagodic M. MicroRNAs as promising novel biomarkers and potential drug targets for inflammatory neurological diseases. J Neurol Sci. 2015 Sep 15;356(1-2):3-4.
Castelo-Branco G, Stridh P, Guerreiro-Cacais AO, Adzemovic MZ, Falcão AM, Marta M, Berglund R, Gillett A, Hamza KH, Lassmann H, Hermanson O, Jagodic M. Acute treatment with valproic acid and l-thyroxine ameliorates clinical signs of experimental autoimmune encephalomyelitis and prevents brain pathology in DA rats. Neurobiol Dis. 2014 Nov;71:220-33. doi: 10.1016/j.nbd.2014.08.019. Epub 2014 Aug 19. PubMed PMID: 25149263.
Stridh P, Ruhrmann S, Bergman P, Thessén Hedreul M, Flytzani S, Beyeen AD, Gillett A, Krivosija N, Öckinger J, Ferguson-Smith AC, Jagodic M. Parent-of-origin effects implicate epigenetic regulation of experimental autoimmune encephalomyelitis and identify imprinted Dlk1 as a novel risk gene. PLoS Genet. 2014 Mar 27;10(3):e1004265. doi: 10.1371/journal.pgen.1004265.
eCollection 2014 Mar. PubMed PMID: 24676147; PubMed Central PMCID: PMC3967983
Gillett A1, Bergman P, Parsa R, Bremges A, Giegerich R, Jagodic M. A silent exonic SNP in kdm3a affects nucleic acids structure but does not regulate experimental autoimmune encephalomyelitis. PLoS One. 2013 Dec 3;8(12):e81912.
Adzemovic MZ, Zeitelhofer M, Hochmeister S, Gustafsson SA, Jagodic M. Efficacy of vitamin D in treating multiple sclerosis-like neuroinflammation depends on developmental stage. Exp Neurol. 2013 Nov;249:39-48.
Thessen Hedreul M, Möller S, Stridh P, Gupta Y, Gillett A, Daniel Beyeen A, Öckinger J, Flytzani S, Diez M, Olsson T, Jagodic M. Combining genetic mapping with genome-wide expression in experimental autoimmune encephalomyelitis highlights a gene network enriched for T cell functions and candidate genes regulating autoimmunity. Hum Mol Genet. 2013 Dec 15;22(24):4952-66.
Rat Genome Sequencing and Mapping Consortium. Combined sequence-based and genetic mapping analysis of complex traits in outbred rats. Nat Genet. 2013 Jul;45(7):767-75. doi: 10.1038/ng.2644. Epub 2013 May 26. PubMed PMID: 23708188; PubMed Central PMCID: PMC3821058
International Multiple Sclerosis Genetics Consortium (IMSGC). Combined sequence-based and genetic mapping analysis of complex traits in outbred rats. Nat Genet. 2013 Jul;45(7):767-75.
Bergman P, James T, Kular L, Ruhrmann S, Kramarova T, Kvist A, Supic G, Gillett A, Pivarcsi A, Jagodic M. Next-generation sequencing identifies microRNAs that associate with pathogenic autoimmune neuroinflammation in rats. J Immunol. 2013 Apr 15;190(8):4066-75.
Marabita F, Almgren M, Lindholm ME, Ruhrmann S, Fagerström-Billai F, Jagodic M, Sundberg CJ, Ekström TJ, Teschendorff AE, Tegnér J, Gomez-Cabrero D. An evaluation of analysis pipelines for DNA methylation profiling using the Illumina HumanMethylation450 BeadChip platform. Epigenetics. 2013 Mar;8(3):333-46.
Colacios C, Casemayou A, Dejean AS, Gaits-Iacovoni F, Pedros C, Bernard I, Lagrange D, Deckert M, Lamouroux L, Jagodic M, Olsson T, Liblau RS, Fournié GJ, Saoudi A. The p.Arg63Trp polymorphism controls Vav1 functions and Foxp3 regulatory T cell development. J Exp Med. 2011 Oct 4;208(11):2183-91. doi:10.1084/jem.20102191. Epub 2011 Sep 26. PubMed PMID: 21948080; PubMed Central PMCID: PMC3201202
International Multiple Sclerosis Genetics Consortium (IMSGC). Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011 Aug 10;476(7359):214-9.
Jagodic M, Colacios C, Nohra R, Dejean AS, Beyeen AD, Khademi M, Casemayou A, Lamouroux L, Duthoit C, Papapietro O, Sjöholm L, Bernard I, Lagrange D, Dahlman I, Lundmark F, Oturai AB, Soendergaard HB, Kemppinen A, Saarela J, Tienari PJ, Harbo HF, Spurkland A, Ramagopalan SV, Sadovnick DA, Ebers GC, Seddighzadeh M, Klareskog L, Alfredsson L, Padyukov L, Hillert J, Clanet M, Edan G, Fontaine B, Fournié GJ, Kockum I, Saoudi A, Olsson T. A role for VAV1 in experimental autoimmune encephalomyelitis and multiple sclerosis. Sci Transl Med. 2009 Dec 9;1(10):10ra21.