From methylation to myelination: epigenomic and transcriptomic profiling of chronic inactive demyelinated multiple sclerosis lesions.

Tiane, Assia; Schepers, Melissa; Reijnders, Rick A.; van Veggel, Lieve; Chenine, Sarah; Rombaut, Ben; Dempster, Emma; Verfaillie, Catherine; Wasner, Kobi; Grünewald, Anne; Prickaerts, Jos; Pishva, Ehsan; Hellings, Niels; van den Hove, Daniel; Vanmierlo, Tim

doi:10.1007/s00401-023-02596-8

Article (Scientific journals)

From methylation to myelination: epigenomic and transcriptomic profiling of chronic inactive demyelinated multiple sclerosis lesions.

Tiane, Assia; Schepers, Melissa; Reijnders, Rick A. et al.

2023 • In Acta Neuropathologica

Peer Reviewed verified by ORBi

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https://hdl.handle.net/10993/55307

DOI
10.1007/s00401-023-02596-8

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37286732

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Keywords :

Epigenetic editing; Epigenetics; Oligodendrocyte; Progressive MS

Abstract :

[en] In the progressive phase of multiple sclerosis (MS), the hampered differentiation capacity of oligodendrocyte precursor cells (OPCs) eventually results in remyelination failure. We have previously shown that DNA methylation of Id2/Id4 is highly involved in OPC differentiation and remyelination. In this study, we took an unbiased approach by determining genome-wide DNA methylation patterns within chronically demyelinated MS lesions and investigated how certain epigenetic signatures relate to OPC differentiation capacity. We compared genome-wide DNA methylation and transcriptional profiles between chronically demyelinated MS lesions and matched normal-appearing white matter (NAWM), making use of post-mortem brain tissue (n = 9/group). DNA methylation differences that inversely correlated with mRNA expression of their corresponding genes were validated for their cell-type specificity in laser-captured OPCs using pyrosequencing. The CRISPR-dCas9-DNMT3a/TET1 system was used to epigenetically edit human-iPSC-derived oligodendrocytes to assess the effect on cellular differentiation. Our data show hypermethylation of CpGs within genes that cluster in gene ontologies related to myelination and axon ensheathment. Cell type-specific validation indicates a region-dependent hypermethylation of MBP, encoding for myelin basic protein, in OPCs obtained from white matter lesions compared to NAWM-derived OPCs. By altering the DNA methylation state of specific CpGs within the promotor region of MBP, using epigenetic editing, we show that cellular differentiation and myelination can be bidirectionally manipulated using the CRISPR-dCas9-DNMT3a/TET1 system in vitro. Our data indicate that OPCs within chronically demyelinated MS lesions acquire an inhibitory phenotype, which translates into hypermethylation of crucial myelination-related genes. Altering the epigenetic status of MBP can restore the differentiation capacity of OPCs and possibly boost (re)myelination.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Tiane, Assia

Schepers, Melissa

Reijnders, Rick A.

van Veggel, Lieve

Chenine, Sarah

Rombaut, Ben

Dempster, Emma

Verfaillie, Catherine

Wasner, Kobi

Grünewald, Anne ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology

More authors (5 more)

External co-authors :

yes

Language :

English

Title :

From methylation to myelination: epigenomic and transcriptomic profiling of chronic inactive demyelinated multiple sclerosis lesions.

Publication date :

2023

Journal title :

Acta Neuropathologica

ISSN :

1432-0533

Publisher :

Springer, Germany

Peer reviewed :

Peer Reviewed verified by ORBi

FnR Project :

FNR9631103 - Modelling Idiopathic Parkinson'S Disease-associated Somatic Variation In Dopaminergic Neurons, 2015 (01/01/2016-31/12/2022) - Anne Grünewald

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Bibliography

Andrews S (2010) FastQC: a quality control tool for high throughput sequence data. http://www.bioinformatics.babraham.ac.uk/projects/fastqc
Aronesty E (2011) ea-utils: command-line tools for processing biological sequencing data. https://github.com/ExpressionAnalysis/ea-utils
Aryee MJ, Jaffe AE, Corrada-Bravo H, Ladd-Acosta C, Feinberg AP, Hansen KD et al (2014) Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics 30:1363–1369. 10.1093/bioinformatics/btu049 DOI: 10.1093/bioinformatics/btu049
Bechler ME (2019) A neuron-free microfiber assay to assess myelin sheath formation. Methods Mol Biol 1936:97–110. 10.1007/978-1-4939-9072-6_6 DOI: 10.1007/978-1-4939-9072-6_6
Berry K, Wang J, Lu QR (2020) Epigenetic regulation of oligodendrocyte myelination in developmental disorders and neurodegenerative diseases. F1000Res. 10.12688/f1000research.20904.1 DOI: 10.12688/f1000research.20904.1
Boggs JM, Rangaraj G, Heng YM, Liu Y, Harauz G (2011) Myelin basic protein binds microtubules to a membrane surface and to actin filaments in vitro: effect of phosphorylation and deimination. Biochim Biophys Acta 1808:761–773. 10.1016/j.bbamem.2010.12.016 DOI: 10.1016/j.bbamem.2010.12.016
Boggs JM, Rangaraj G, Hill CM, Bates IR, Heng YM, Harauz G (2005) Effect of arginine loss in myelin basic protein, as occurs in its deiminated charge isoform, on mediation of actin polymerization and actin binding to a lipid membrane in vitro. Biochemistry 44:3524–3534. 10.1021/bi0473760 DOI: 10.1021/bi0473760
Celarain N, Tomas-Roig J (2020) Aberrant DNA methylation profile exacerbates inflammation and neurodegeneration in multiple sclerosis patients. J Neuroinflammation 17:21. 10.1186/s12974-019-1667-1 DOI: 10.1186/s12974-019-1667-1
Chomyk AM, Volsko C, Tripathi A, Deckard SA, Trapp BD, Fox RJ et al (2017) DNA methylation in demyelinated multiple sclerosis hippocampus. Sci Rep 7:8696. 10.1038/s41598-017-08623-5 DOI: 10.1038/s41598-017-08623-5
Dansu DK, Sauma S, Casaccia P (2021) Oligodendrocyte progenitors as environmental biosensors. Semin Cell Dev Biol 116:38–44. 10.1016/j.semcdb.2020.09.012 DOI: 10.1016/j.semcdb.2020.09.012
Dyer CA, Phillbotte T, Wolf MK, Billings-Gagliardi S (1997) Regulation of cytoskeleton by myelin components: studies on shiverer oligodendrocytes carrying an Mbp transgene. Dev Neurosci 19:395–409. 10.1159/000111237 DOI: 10.1159/000111237
Dzięgiel P, Owczarek T, Plazuk E, Gomułkiewicz A, Majchrzak M, Podhorska-Okołów M et al (2010) Ceramide galactosyltransferase (UGT8) is a molecular marker of breast cancer malignancy and lung metastases. Br J Cancer 103:524–531. 10.1038/sj.bjc.6605750 DOI: 10.1038/sj.bjc.6605750
Fard MK, van der Meer F, Sánchez P, Cantuti-Castelvetri L, Mandad S, Jäkel S et al (2017) BCAS1 expression defines a population of early myelinating oligodendrocytes in multiple sclerosis lesions. Sci Transl Med. 10.1126/scitranslmed.aam7816 DOI: 10.1126/scitranslmed.aam7816
Franklin RJ, Ffrench-Constant C (2008) Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci 9:839–855. 10.1038/nrn2480 DOI: 10.1038/nrn2480
García-Díaz B, Riquelme R, Varela-Nieto I, Jiménez AJ, de Diego I, Gómez-Conde AI et al (2015) Loss of lysophosphatidic acid receptor LPA1 alters oligodendrocyte differentiation and myelination in the mouse cerebral cortex. Brain Struct Funct 220:3701–3720. 10.1007/s00429-014-0885-7 DOI: 10.1007/s00429-014-0885-7
Garcia-Leon JA, Garcia-Diaz B, Eggermont K, Caceres-Palomo L, Neyrinck K, Madeiro da Costa R et al (2020) Generation of oligodendrocytes and establishment of an all-human myelinating platform from human pluripotent stem cells. Nat Protoc 15:3716–3744. 10.1038/s41596-020-0395-4 DOI: 10.1038/s41596-020-0395-4
Gruchot J, Weyers V, Göttle P, Förster M, Hartung H-P, Küry P et al (2019) The molecular basis for remyelination failure in multiple sclerosis. Cells 8:825. 10.3390/cells8080825 DOI: 10.3390/cells8080825
Harauz G, Boggs JM (2013) Myelin management by the 18.5-kDa and 21.5-kDa classic myelin basic protein isoforms. J Neurochem 125:334–361. 10.1111/jnc.12195 DOI: 10.1111/jnc.12195
Hill CM, Harauz G (2005) Charge effects modulate actin assembly by classic myelin basic protein isoforms. Biochem Biophys Res Commun 329:362–369. 10.1016/j.bbrc.2005.01.151 DOI: 10.1016/j.bbrc.2005.01.151
Hill CM, Libich DS, Harauz G (2005) Assembly of tubulin by classic myelin basic protein isoforms and regulation by post-translational modification. Biochemistry 44:16672–16683. 10.1021/bi050646+ DOI: 10.1021/bi050646+
Houseman EA, Molitor J, Marsit CJ (2014) Reference-free cell mixture adjustments in analysis of DNA methylation data. Bioinformatics 30:1431–1439. 10.1093/bioinformatics/btu029 DOI: 10.1093/bioinformatics/btu029
Hudish LI, Blasky AJ, Appel B (2013) miR-219 regulates neural precursor differentiation by direct inhibition of apical par polarity proteins. Dev Cell 27:387–398. 10.1016/j.devcel.2013.10.015 DOI: 10.1016/j.devcel.2013.10.015
Huynh JL, Garg P, Thin TH, Yoo S, Dutta R, Trapp BD et al (2014) Epigenome-wide differences in pathology-free regions of multiple sclerosis-affected brains. Nat Neurosci 17:121–130. 10.1038/nn.3588 DOI: 10.1038/nn.3588
Kim D, Paggi JM, Park C, Bennett C, Salzberg SL (2019) Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype. Nat Biotechnol 37:907–915. 10.1038/s41587-019-0201-4 DOI: 10.1038/s41587-019-0201-4
Koulousakis P, Tiane A, Hellings N, Prickaerts J, van den Hove D, Vanmierlo T (2023) A perspective on causality assessment in epigenetic research on neurodegenerative disorders. Neural Regen Res 18:331–332. 10.4103/1673-5374.343898 DOI: 10.4103/1673-5374.343898
Krämer-Albers E-M, White R (2011) From axon–glial signalling to myelination: the integrating role of oligodendroglial Fyn kinase. Cell Mol Life Sci 68:2003–2012. 10.1007/s00018-010-0616-z DOI: 10.1007/s00018-010-0616-z
Kressler C, Gasparoni G, Nordström K, Hamo D, Salhab A, Dimitropoulos C et al (2020) Targeted de-methylation of the FOXP3-TSDR is sufficient to induce physiological FOXP3 expression but not a functional treg phenotype. Front Immunol 11:609891. 10.3389/fimmu.2020.609891 DOI: 10.3389/fimmu.2020.609891
Kular L, Ewing E, Needhamsen M, Pahlevan Kakhki M, Covacu R, Gomez-Cabrero D et al (2022) DNA methylation changes in glial cells of the normal-appearing white matter in multiple sclerosis patients. Epigenetics. 10.1080/15592294.2021.2020436 DOI: 10.1080/15592294.2021.2020436
Kular L, Jagodic M (2020) Epigenetic insights into multiple sclerosis disease progression. J Intern Med 288:82–102. 10.1111/joim.13045 DOI: 10.1111/joim.13045
Kular L, Needhamsen M, Adzemovic MZ, Kramarova T, Gomez-Cabrero D, Ewing E et al (2019) Neuronal methylome reveals CREB-associated neuro-axonal impairment in multiple sclerosis. Clin Epigenetics 11:86. 10.1186/s13148-019-0678-1 DOI: 10.1186/s13148-019-0678-1
Leek JT, Johnson WE, Parker HS, Jaffe AE, Storey JD (2012) The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics 28:882–883. 10.1093/bioinformatics/bts034 DOI: 10.1093/bioinformatics/bts034
Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N et al (2009) The Sequence Alignment/Map format and SAMtools. Bioinformatics 25:2078–2079. 10.1093/bioinformatics/btp352 DOI: 10.1093/bioinformatics/btp352
Lin L, Liu Y, Xu F, Huang J, Daugaard TF, Petersen TS et al (2018) Genome-wide determination of on-target and off-target characteristics for RNA-guided DNA methylation by dCas9 methyltransferases. Gigascience 7:1–19. 10.1093/gigascience/giy011 DOI: 10.1093/gigascience/giy011
Loma I, Heyman R (2011) Multiple sclerosis: pathogenesis and treatment. Curr Neuropharmacol 9:409–416. 10.2174/157015911796557911 DOI: 10.2174/157015911796557911
McCartney DL, Walker RM, Morris SW, McIntosh AM, Porteous DJ, Evans KL (2016) Identification of polymorphic and off-target probe binding sites on the Illumina Infinium MethylationEPIC BeadChip. Genom Data 9:22–24. 10.1016/j.gdata.2016.05.012 DOI: 10.1016/j.gdata.2016.05.012
Moyon S, Huynh JL, Dutta D, Zhang F, Ma D, Yoo S et al (2016) Functional characterization of DNA methylation in the oligodendrocyte lineage. Cell Rep 15:748–760. 10.1016/j.celrep.2016.03.060 DOI: 10.1016/j.celrep.2016.03.060
Moyon S, Ma D, Huynh JL, Coutts DJC, Zhao C, Casaccia P et al (2017) Efficient remyelination requires DNA methylation. eNeuro. 10.1523/eneuro.0336-16.2017 DOI: 10.1523/eneuro.0336-16.2017
Müller C, Bauer N, Schäfer I, White R (2013) Making myelin basic protein—from mRNA transport to localized translation. Front Cell Neurosci. 10.3389/fncel.2013.00169 DOI: 10.3389/fncel.2013.00169
Neyrinck K, Garcia-Leon JA (2021) Single transcription factor-based differentiation allowing fast and efficient oligodendrocyte generation via SOX10 overexpression. Methods Mol Biol 2352:149–170. 10.1007/978-1-0716-1601-7_11 DOI: 10.1007/978-1-0716-1601-7_11
Pidsley R, Wong CCY, Volta M, Lunnon K, Mill J, Schalkwyk LC (2013) A data-driven approach to preprocessing Illumina 450K methylation array data. BMC Genom 14:293. 10.1186/1471-2164-14-293 DOI: 10.1186/1471-2164-14-293
Popescu BFG, Pirko I, Lucchinetti CF (2013) Pathology of multiple sclerosis: where do we stand? Continuum (Minneapolis, Minn) 19:901–921. 10.1212/01.CON.0000433291.23091.65 DOI: 10.1212/01.CON.0000433291.23091.65
Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W et al (2015) limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43:e47. 10.1093/nar/gkv007 DOI: 10.1093/nar/gkv007
Samudyata C-B, Liu J (2020) Epigenetic regulation of oligodendrocyte differentiation: from development to demyelinating disorders. Glia 68:1619–1630. 10.1002/glia.23820 DOI: 10.1002/glia.23820
Seiwa C, Kojima-Aikawa K, Matsumoto I, Asou H (2002) CNS myelinogenesis in vitro: myelin basic protein deficient shiverer oligodendrocytes. J Neurosci Res 69:305–317. 10.1002/jnr.10291 DOI: 10.1002/jnr.10291
Shen S, Sandoval J, Swiss VA, Li J, Dupree J, Franklin RJM et al (2008) Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency. Nat Neurosci 11:1024–1034. 10.1038/nn.2172 DOI: 10.1038/nn.2172
Smith RG, Pishva E, Shireby G, Smith AR, Roubroeks JAY, Hannon E et al (2021) A meta-analysis of epigenome-wide association studies in Alzheimer’s disease highlights novel differentially methylated loci across cortex. Nat Commun 12:3517. 10.1038/s41467-021-23243-4 DOI: 10.1038/s41467-021-23243-4
Tanaka Y, Yamada K, Zhou CJ, Ban N, Shioda S, Inagaki N (2003) Temporal and spatial profiles of ABCA2-expressing oligodendrocytes in the developing rat brain. J Comp Neurol 455:353–367. 10.1002/cne.10493 DOI: 10.1002/cne.10493
Tiane A, Schepers M, Riemens R, Rombaut B, Vandormael P, Somers V et al (2021) DNA methylation regulates the expression of the negative transcriptional regulators ID2 and ID4 during OPC differentiation. Cell Mol Life Sci 78:6631–6644. 10.1007/s00018-021-03927-2 DOI: 10.1007/s00018-021-03927-2
Tiane A, Schepers M, Rombaut B, Hupperts R, Prickaerts J, Hellings N et al (2019) From OPC to oligodendrocyte: an epigenetic journey. Cells. 10.3390/cells8101236 DOI: 10.3390/cells8101236
Vojta A, Dobrinić P, Tadić V, Bočkor L, Korać P, Julg B et al (2016) Repurposing the CRISPR-Cas9 system for targeted DNA methylation. Nucleic Acids Res 44:5615–5628. 10.1093/nar/gkw159 DOI: 10.1093/nar/gkw159
Xie N, Zhou Y, Sun Q, Tang B (2018) Novel epigenetic techniques provided by the CRISPR/Cas9 system. Stem Cells Int 2018:7834175. 10.1155/2018/7834175 DOI: 10.1155/2018/7834175
Zheleznyakova GY, Piket E, Marabita F, Kakhki MP, Ewing E, Ruhrmann S et al (2017) Epigenetic research in multiple sclerosis: progress, challenges, and opportunities. Physiol Genom 49:447–461. 10.1152/physiolgenomics.00060.2017 DOI: 10.1152/physiolgenomics.00060.2017
Zoupi L, Savvaki M, Kalemaki K, Kalafatakis I, Sidiropoulou K, Karagogeos D (2018) The function of contactin-2/TAG-1 in oligodendrocytes in health and demyelinating pathology. Glia 66:576–591. 10.1002/glia.23266 DOI: 10.1002/glia.23266
Zurawski J, Stankiewicz J (2018) Multiple sclerosis re-examined: essential and emerging clinical concepts. Am J Med 131:464–472. 10.1016/j.amjmed.2017.11.044 DOI: 10.1016/j.amjmed.2017.11.044