Maja Jagodic's research group

Epigenetic origins and mechanisms in neuroinflammation

Photo: N/A

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).

    Photo: N/A

    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.

    Research projects

    • DNA methylation and ncRNA changes as a functional consequence of etiological genetic (MS risk genes) and environmental (e.g. smoking and vitamin D) factors
    • DNA methylation that controls phenotype of pathogenic immune cells and cells targeted in the CNS
    • Functional mechanisms of epigenetic changes in neuroinflammation
    • Potentials of ‘epigenetic medicine’: biomarkers (e.g. DNA methylation and miRNAs) and treatments (e.g. HDAC inhibitors)

    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.

    Selected publications

    For full list of publications please visit Google Scholar link

    Microglial autophagy-associated phagocytosis is essential for recovery from neuroinflammation.
    Berglund R, Guerreiro-Cacais AO, Adzemovic MZ, Zeitelhofer M, Lund H, Ewing E, et al
    Sci Immunol 2020 10;5(52):

    C-type lectin receptors Mcl and Mincle control development of multiple sclerosis-like neuroinflammation.
    N'diaye M, Brauner S, Flytzani S, Kular L, Warnecke A, Adzemovic MZ, et al
    J Clin Invest 2020 02;130(2):838-852

    Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility.

    Science 2019 09;365(6460):

    Different epigenetic clocks reflect distinct pathophysiological features of multiple sclerosis.
    Theodoropoulou E, Alfredsson L, Piehl F, Marabita F, Jagodic M
    Epigenomics 2019 09;11(12):1429-1439

    Tobacco smoking induces changes in true DNA methylation, hydroxymethylation and gene expression in bronchoalveolar lavage cells.
    Ringh MV, Hagemann-Jensen M, Needhamsen M, Kular L, Breeze CE, Sjöholm LK, et al
    EBioMedicine 2019 Aug;46():290-304

    Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes.
    Carlström KE, Ewing E, Granqvist M, Gyllenberg A, Aeinehband S, Enoksson SL, et al
    Nat Commun 2019 07;10(1):3081

    Neuronal methylome reveals CREB-associated neuro-axonal impairment in multiple sclerosis.
    Kular L, Needhamsen M, Adzemovic MZ, Kramarova T, Gomez-Cabrero D, Ewing E, et al
    Clin Epigenetics 2019 05;11(1):86

    Combining evidence from four immune cell types identifies DNA methylation patterns that implicate functionally distinct pathways during Multiple Sclerosis progression.
    Ewing E, Kular L, Fernandes SJ, Karathanasis N, Lagani V, Ruhrmann S, et al
    EBioMedicine 2019 May;43():411-423

    Small non-coding RNAs as important players, biomarkers and therapeutic targets in multiple sclerosis: A comprehensive overview.
    Piket E, Zheleznyakova GY, Kular L, Jagodic M
    J Autoimmun 2019 07;101():17-25

    DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis.
    Kular L, Liu Y, Ruhrmann S, Zheleznyakova G, Marabita F, Gomez-Cabrero D, et al
    Nat Commun 2018 06;9(1):2397

    Fatal demyelinating disease is induced by monocyte-derived macrophages in the absence of TGF-β signaling.
    Lund H, Pieber M, Parsa R, Grommisch D, Ewing E, Kular L, et al
    Nat. Immunol. 2018 05;19(5):1-7

    Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis ‬.
    Zeitelhofer M, Adzemovic M, Gomez-Cabrero D, Bergman P, Hochmeister S, N'diaye M, et al
    Proc. Natl. Acad. Sci. U.S.A. 2017 02;114(9):E1678-E1687

    Smoking induces DNA methylation changes in Multiple Sclerosis patients with exposure-response relationship.
    Marabita F, Almgren M, Sjöholm L, Kular L, Liu Y, James T, et al
    Sci Rep 2017 Nov;7(1):14589

    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.
    Ruhrmann S, Ewing E, Piket E, Kular L, Cetrulo Lorenzi J, Fernandes S, et al
    Mult. Scler. 2018 Sep;24(10):1288-1300

    Circulating miR-150 in CSF is a novel candidate biomarker for multiple sclerosis.
    Bergman P, Piket E, Khademi M, James T, Brundin L, Olsson T, et al
    Neurol Neuroimmunol Neuroinflamm 2016 Jun;3(3):e219

    Efficacy of vitamin D in treating multiple sclerosis-like neuroinflammation depends on developmental stage.
    Adzemovic M, Zeitelhofer M, Hochmeister S, Gustafsson S, Jagodic M
    Exp. Neurol. 2013 Nov;249():39-48

    Acute treatment with valproic acid and l-thyroxine ameliorates clinical signs of experimental autoimmune encephalomyelitis and prevents brain pathology in DA rats.
    Castelo-Branco G, Stridh P, Guerreiro-Cacais A, Adzemovic M, Falcão A, Marta M, et al
    Neurobiol. Dis. 2014 Nov;71():220-33

    Parent-of-origin effects implicate epigenetic regulation of experimental autoimmune encephalomyelitis and identify imprinted Dlk1 as a novel risk gene.
    Stridh P, Ruhrmann S, Bergman P, Thessén Hedreul M, Flytzani S, Beyeen A, et al
    PLoS Genet. 2014 Mar;10(3):e1004265

    Combined sequence-based and genetic mapping analysis of complex traits in outbred rats.
    , Baud A, Hermsen R, Guryev V, Stridh P, Graham D, et al
    Nat. Genet. 2013 Jul;45(7):767-75

    Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.
    , , Sawcer S, Hellenthal G, Pirinen M, Spencer C, et al
    Nature 2011 Aug;476(7359):214-9

    A role for VAV1 in experimental autoimmune encephalomyelitis and multiple sclerosis.
    Jagodic M, Colacios C, Nohra R, Dejean A, Beyeen A, Khademi M, et al
    Sci Transl Med 2009 Dec;1(10):10ra21

    Group members

    Current funding

    • Horizon2020 EU/IMI2 "EUbOPEN" grant
    • Knut and Alice Wallenberg Foundation
    • European Research Council consolidator (ERC-CoG) grant 
    • The Swedish Research Council (VR)
    • EU/Horizon2020 (co-coordinator)
    • Karolinska Institutet Senior Research Fellow Grant
    • Karolinska Institutet KID-grants
    • The regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet
    • AstraZeneca/SciLifeLab Joint Research Collaboration (co-applicant)
    • The Swedish Brain Foundation
    • The NEURO fund

    News

    Interview with Maja Jagodic in Swedish Television for the new program Rapport, on September 3rd 2020

    KI News, October 16 2020: Study explains the process that exacerbates MS

    Interview with Maja Jagodic, published 2020 at the Knut and Alice Wallenberg Foundation website

    Mechanism controlling multiple sclerosis risk identified
    https://ki.se/en/news/mechanism-controlling-multiple-sclerosis-risk-identified
    https://www.sciencedaily.com/releases/2018/06/180619122530.htm

    Smoking induces DNA methylation changes in multiple sclerosis patients
    https://multiplesclerosisnewstoday.com/2017/11/22/study-confirms-that-smoking-affects-process-linked-to-ms-patients-gene-activity/

    MultipleMS
    https://www.multiplems.eu/

    Best PI at KI award
    https://sites.google.com/site/kipostdocsorganization/news