{"entity": "researcher", "timestamp": "2026-07-15T16:20:58.488Z", "family": "Jagodic", "given": "Maja", "initials": "M", "orcid": "0000-0003-0756-889X", "affiliations": ["Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden. maja.jagodic@ki.se."], "links": {"self": {"href": "https://publications.scilifelab.se/researcher/b651ef39c6b0436992e2305f425eba72.json"}, "display": {"href": "https://publications.scilifelab.se/researcher/b651ef39c6b0436992e2305f425eba72"}}, "publications": [{"entity": "publication", "iuid": "59eca9ec25b940089924c25b003d94a3", "links": {"self": {"href": "https://publications.scilifelab.se/publication/59eca9ec25b940089924c25b003d94a3.json"}, "display": {"href": "https://publications.scilifelab.se/publication/59eca9ec25b940089924c25b003d94a3"}}, "title": "Single-nucleus epigenomic profiling of the adult human central nervous system unveils epigenetic memory of developmental programs.", "authors": [{"family": "Kabbe", "given": "Mukund", "initials": "M"}, {"family": "Agirre", "given": "Eneritz", "initials": "E", "orcid": "0000-0002-5012-0305", "researcher": {"href": "https://publications.scilifelab.se/researcher/a507b19745c64c3bb8ef5dce800c8687.json"}}, {"family": "Carlstr\u00f6m", "given": "Karl E", "initials": "KE", "orcid": "0000-0002-3001-2403", "researcher": {"href": "https://publications.scilifelab.se/researcher/3aa5f65acad34b5790a2b9f607521825.json"}}, {"family": "Dumral", "given": "\u00d6zge", "initials": "\u00d6", "orcid": "0000-0002-9980-2702", "researcher": {"href": "https://publications.scilifelab.se/researcher/8288edd47f70479e93e1fc441d486997.json"}}, {"family": "Lor", "given": "Yuk Kit", "initials": "YK"}, {"family": "Pohl", "given": "Fabio Baldivia", "initials": "FB", "orcid": "0000-0003-1695-4936", "researcher": {"href": "https://publications.scilifelab.se/researcher/c7913023dd124c8f96f5d072af0eff56.json"}}, {"family": "Ruffin", "given": "Nicolas", "initials": "N", "orcid": "0000-0002-3698-5505", "researcher": {"href": "https://publications.scilifelab.se/researcher/991af3c2719f4c0b9d4feeae24c5161a.json"}}, {"family": "van Bruggen", "given": "David", "initials": "D"}, {"family": "Meijer", "given": "Mandy", "initials": "M"}, {"family": "Seeker", "given": "Luise A", "initials": "LA"}, {"family": "Bestard-Cuche", "given": "Nadine", "initials": "N"}, {"family": "Lederer", "given": "Alex R", "initials": "AR", "orcid": "0000-0001-6381-5088", "researcher": {"href": "https://publications.scilifelab.se/researcher/fa3aa57bbddf4845b2d2c438ecfb2bff.json"}}, {"family": "Zhang", "given": "Jilin", "initials": "J"}, {"family": "Ahola", "given": "Virpi", "initials": "V"}, {"family": "Goldman", "given": "Steven A", "initials": "SA"}, {"family": "Edstr\u00f6m", "given": "Erik", "initials": "E"}, {"family": "Arvidsson", "given": "Lisa", "initials": "L", "orcid": "0000-0003-2129-5357", "researcher": {"href": "https://publications.scilifelab.se/researcher/654ca67f559842669ed19aefa16f878b.json"}}, {"family": "Moreira", "given": "Tiago Holm", "initials": "TH"}, {"family": "Bartosovic", "given": "Marek", "initials": "M", "orcid": "0000-0003-2057-6050", "researcher": {"href": "https://publications.scilifelab.se/researcher/ce3c36916eb844e7bc10f73b95f6494a.json"}}, {"family": "Jagodic", "given": "Maja", "initials": "M", "orcid": "0000-0003-0756-889X", "researcher": {"href": "https://publications.scilifelab.se/researcher/b651ef39c6b0436992e2305f425eba72.json"}}, {"family": "Williams", "given": "Anna", "initials": "A", "orcid": "0000-0002-6329-382X", "researcher": {"href": "https://publications.scilifelab.se/researcher/80c29c92194a4af3a6ed8f9d18dbddfe.json"}}, {"family": "Castelo-Branco", "given": "Gon\u00e7alo", "initials": "G", "orcid": "0000-0003-2247-9393", "researcher": {"href": "https://publications.scilifelab.se/researcher/10b1a8fb48114340b8e390ca1f9e3321.json"}}], "type": "journal article", "published": "2026-03-19", "journal": {"title": "Nat. Neurosci.", "issn": "1546-1726", "issn-l": "1097-6256"}, "abstract": "Neural cells in the adult human central nervous system (CNS) display extensive transcriptional heterogeneity. How different layers of epigenetic regulation underpin this heterogeneity is poorly understood. Here we profile, at the single-nuclei epigenomic level, distinct regions of the adult human CNS, for chromatin accessibility and simultaneously for the histone modifications H3K27me3 and H3K27ac. We unveil a putative SOX10 enhancer and primed chromatin signatures at HOX loci in spinal-cord-derived human oligodendroglia (OLG) and astrocytes, but not microglia. These signatures in adult OLG were reminiscent of developmental profiles but were decoupled from robust gene expression. Moreover, using high-resolution Micro-C, we show that induced pluripotent stem-cell-derived human OLGs exhibit a HOX chromatin architecture compatible with the primed chromatin in adult OLGs, bearing a strong resemblance not only to OLG developmental architecture but also to high-grade pontine gliomas. Thus, epigenetic memory from developmental states in adult OLG not only enables them to promptly transcribe Hox family genes during regeneration but also makes them susceptible to gliomagenesis.", "doi": "10.1038/s41593-026-02208-0", "pmid": "41857393", "labels": {"National Genomics Infrastructure": "Service", "NGI Stockholm (Genomics Production)": "Service", "NGI Short read": "Service"}, "xrefs": [{"db": "pii", "key": "10.1038/s41593-026-02208-0"}], "notes": [], "created": "2026-03-23T13:16:33.192Z", "modified": "2026-03-23T13:16:34.150Z"}, {"entity": "publication", "iuid": "2eb354120b4e4f18a6b6912af75d7656", "links": {"self": {"href": "https://publications.scilifelab.se/publication/2eb354120b4e4f18a6b6912af75d7656.json"}, "display": {"href": "https://publications.scilifelab.se/publication/2eb354120b4e4f18a6b6912af75d7656"}}, "title": "Comprehensive profiling of CRISPR/dCas9 epigenome editors indicates a complex link between on and off target effects", "authors": [{"family": "Pahlevan Kakhki", "given": "Majid", "initials": "M", "orcid": "0000-0002-5407-3147", "researcher": {"href": "https://publications.scilifelab.se/researcher/5f376c85cfbe4711ae41d9ee5ade8f09.json"}}, {"family": "Rangani", "given": "Fatemeh", "initials": "F"}, {"family": "Ewing", "given": "Ewoud", "initials": "E", "orcid": "0000-0001-8644-366X", "researcher": {"href": "https://publications.scilifelab.se/researcher/aea9350a4f864d8e8781ab111b4f9273.json"}}, {"family": "Starvaggi Cucuzza", "given": "Chiara", "initials": "C", "orcid": "0000-0002-9088-7658", "researcher": {"href": "https://publications.scilifelab.se/researcher/0ead2e8f98754d1586891eda5adb9e1a.json"}}, {"family": "Zheleznyakova", "given": "Galina", "initials": "G"}, {"family": "Kalomoiri", "given": "Maria", "initials": "M"}, {"family": "Kenny", "given": "Lea", "initials": "L"}, {"family": "Raghavan", "given": "Anika", "initials": "A"}, {"family": "Rao Prakash", "given": "Chandana", "initials": "C"}, {"family": "van den Hoeven", "given": "Gabe", "initials": "G"}, {"family": "Venkata S. Badam", "given": "Tejaswi", "initials": "T"}, {"family": "Covacu", "given": "Ruxandra", "initials": "R"}, {"family": "Andreou", "given": "Ioanna", "initials": "I"}, {"family": "Needhamsen", "given": "Maria", "initials": "M"}, {"family": "Kular", "given": "Lara", "initials": "L", "orcid": "0000-0002-2907-6071", "researcher": {"href": "https://publications.scilifelab.se/researcher/09563004a20543dc934dd4d3b1ceebd7.json"}}, {"family": "Jagodic", "given": "Maja", "initials": "M", "orcid": "0000-0003-0756-889X", "researcher": {"href": "https://publications.scilifelab.se/researcher/b651ef39c6b0436992e2305f425eba72.json"}}], "type": "journal-article", "published": "2026-01-31", "journal": {"title": "Genome Biol.", "issn": "1474-760X", "issn-l": "1474-7596", "volume": "27", "issue": "1", "pages": null}, "abstract": "CRISPR/dCas9-based epigenome editing systems, including DNA methylation epimodifiers, have greatly advanced molecular functional studies, revolutionizing their precision and applicability. Despite their promise, challenges such as the magnitude and stability of the on-target editing and unwanted off-target effects underscore the need for improved tool characterization and design.\n\nWe systematically compare specific targeting and genome-wide off-target effects of available and novel dCas9-based DNA methylation editing tools over time. We demonstrate that multimerization of the catalytic domain of DNA methyltransferase 3A enhances editing potency but also induces widespread, early methylation deposition at low-to-medium methylated promoter-related regions with specific gRNAs and also with non-targeting gRNAs. A small fraction of the methylation changes associated with transcriptional dysregulation and mapped predominantly to bivalent chromatin associating both with transcriptional repression and activation. Additionally, specific non-targeting control gRNAs cause pervasive and long-lasting methylation-independent transcriptional alterations particularly in genes linked to RNA and energy metabolism. CRISPRoff emerges as the most efficient tool for stable promoter targeting, with fewer and less stable off-target effects compared to other epimodifiers but with persistent transcriptome alterations.\n\nOur findings highlight the delicate balance between potency and specificity of epigenome editing and provide critical insights into the design and application of future tools to improve their precision and minimize unintended consequences.", "doi": "10.1186/s13059-026-03967-6", "pmid": "41620608", "labels": {"National Genomics Infrastructure": "Service", "NGI Stockholm (Genomics Production)": "Service", "NGI Short read": "Service", "NGI SNP genotyping": "Service", "NGI Uppsala (SNP&SEQ Technology Platform)": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC12924462"}, {"db": "pii", "key": "10.1186/s13059-026-03967-6"}], "notes": [], "created": "2026-02-06T08:02:40.826Z", "modified": "2026-03-24T09:10:47.840Z"}, {"entity": "publication", "iuid": "1e5708bc6c1c4c099e773f1d29e68641", "links": {"self": {"href": "https://publications.scilifelab.se/publication/1e5708bc6c1c4c099e773f1d29e68641.json"}, "display": {"href": "https://publications.scilifelab.se/publication/1e5708bc6c1c4c099e773f1d29e68641"}}, "title": "Anoctamin-2-specific T cells link Epstein-Barr virus to multiple sclerosis.", "authors": [{"family": "Thomas", "given": "Olivia G", "initials": "OG", "orcid": "0000-0002-2011-1344", "researcher": {"href": "https://publications.scilifelab.se/researcher/ea07f812ffee4db893c6f98548563525.json"}}, {"family": "Rykaczewska", "given": "Urszula", "initials": "U"}, {"family": "Gale\u0161i\u0107", "given": "Marina", "initials": "M"}, {"family": "van der Burgt", "given": "Rianne T M", "initials": "RTM"}, {"family": "Hall\u00e9n", "given": "Nils", "initials": "N"}, {"family": "Ferro", "given": "Filippo", "initials": "F", "orcid": "0000-0002-6023-8227", "researcher": {"href": "https://publications.scilifelab.se/researcher/27810903638948feb4391fa537a7eda3.json"}}, {"family": "Bronge", "given": "Mattias", "initials": "M", "orcid": "0000-0002-1258-3982", "researcher": {"href": "https://publications.scilifelab.se/researcher/691b77352a57408896ef1fb486980ccd.json"}}, {"family": "Marti", "given": "Zoe", "initials": "Z"}, {"family": "Li", "given": "Yue", "initials": "Y"}, {"family": "Riqu\u00e9", "given": "Alexandra Hill", "initials": "AH"}, {"family": "Lin", "given": "Jianing", "initials": "J"}, {"family": "Krstic", "given": "Aleksa", "initials": "A"}, {"family": "Gromadzka", "given": "Alicja", "initials": "A"}, {"family": "Szonder", "given": "Andr\u00e1s Levente", "initials": "AL"}, {"family": "Sorini", "given": "Chiara", "initials": "C", "orcid": "0000-0002-6803-8377", "researcher": {"href": "https://publications.scilifelab.se/researcher/975173f37f144f06b236817e224de7f0.json"}}, {"family": "Reina-Campos", "given": "Mar\u00eda", "initials": "M"}, {"family": "Sun", "given": "Ting", "initials": "T", "orcid": "0000-0002-7104-7215", "researcher": {"href": "https://publications.scilifelab.se/researcher/521fca43267242fca06da0f5fc823e6a.json"}}, {"family": "Rubio Rodr\u00edguez-Kirby", "given": "Leslie A", "initials": "LA", "orcid": "0000-0003-4467-2661", "researcher": {"href": "https://publications.scilifelab.se/researcher/9790e215a63d40aa8fac497b537999f9.json"}}, {"family": "Dumral", "given": "\u00d6zge", "initials": "\u00d6", "orcid": "0000-0002-9980-2702", "researcher": {"href": "https://publications.scilifelab.se/researcher/8288edd47f70479e93e1fc441d486997.json"}}, {"family": "Berglund", "given": "Rasmus", "initials": "R"}, {"family": "Kakhki", "given": "Majid Pahlevan", "initials": "MP"}, {"family": "Adzemovic", "given": "Milena Z", "initials": "MZ"}, {"family": "Zeitelhofer", "given": "Manuel", "initials": "M"}, {"family": "Akpinar", "given": "Birce", "initials": "B"}, {"family": "Tengvall", "given": "Katarina", "initials": "K", "orcid": "0000-0003-0424-3571", "researcher": {"href": "https://publications.scilifelab.se/researcher/59b02aaaf03b4cd39150c3034888c81d.json"}}, {"family": "Nilsson", "given": "Ola B", "initials": "OB", "orcid": "0000-0002-7516-1760", "researcher": {"href": "https://publications.scilifelab.se/researcher/096ce3bf888b4ad395d53bb3c11f6946.json"}}, {"family": "Holmgren", "given": "Erik", "initials": "E", "orcid": "0000-0002-2656-1864", "researcher": {"href": "https://publications.scilifelab.se/researcher/6160949c45cf4daaab3991d051db5a16.json"}}, {"family": "Cucuzza", "given": "Chiara Starvaggi", "initials": "CS"}, {"family": "H\u00f6gelin", "given": "Klara Asplund", "initials": "KA"}, {"family": "Gafvelin", "given": "Guro", "initials": "G", "orcid": "0000-0003-1618-4011", "researcher": {"href": "https://publications.scilifelab.se/researcher/870294f4604744ccb212a3c299887ecc.json"}}, {"family": "Fink", "given": "Katharina", "initials": "K"}, {"family": "Castelo-Branco", "given": "Gon\u00e7alo", "initials": "G", "orcid": "0000-0003-2247-9393", "researcher": {"href": "https://publications.scilifelab.se/researcher/10b1a8fb48114340b8e390ca1f9e3321.json"}}, {"family": "Needhamsen", "given": "Maria", "initials": "M"}, {"family": "Khademi", "given": "Mohsen", "initials": "M", "orcid": "0000-0003-0801-1444", "researcher": {"href": "https://publications.scilifelab.se/researcher/5446d6d754bc4c429d0e48ade419413c.json"}}, {"family": "Piehl", "given": "Fredrik", "initials": "F", "orcid": "0000-0001-8329-5219", "researcher": {"href": "https://publications.scilifelab.se/researcher/ee04062fbee34836a4fa3f4d2e8076cd.json"}}, {"family": "Gr\u00e4slund", "given": "Torbj\u00f6rn", "initials": "T", "orcid": "0000-0002-5391-600X", "researcher": {"href": "https://publications.scilifelab.se/researcher/52adbc739e274652bbf877facf4f0959.json"}}, {"family": "Alfredsson", "given": "Lars", "initials": "L", "orcid": "0000-0003-1688-6697", "researcher": {"href": "https://publications.scilifelab.se/researcher/6df230614a8a448e8607e03480169658.json"}}, {"family": "Lund", "given": "Harald", "initials": "H", "orcid": "0000-0001-8046-0805", "researcher": {"href": "https://publications.scilifelab.se/researcher/4fe4902c355449e4812008d4ad7a37e0.json"}}, {"family": "Uhl\u00e9n", "given": "Per", "initials": "P", "orcid": "0000-0003-1446-1062", "researcher": {"href": "https://publications.scilifelab.se/researcher/91c3e953634140b8974186ac0d7eac85.json"}}, {"family": "Kockum", "given": "Ingrid", "initials": "I", "orcid": "0000-0002-0867-4726", "researcher": {"href": "https://publications.scilifelab.se/researcher/03ebcc6a01ef4d0db4e4673aff8de5d8.json"}}, {"family": "Martin", "given": "Roland", "initials": "R"}, {"family": "Jagodic", "given": "Maja", "initials": "M", "orcid": "0000-0003-0756-889X", "researcher": {"href": "https://publications.scilifelab.se/researcher/b651ef39c6b0436992e2305f425eba72.json"}}, {"family": "Gr\u00f6nlund", "given": "Hans", "initials": "H", "orcid": "0000-0003-4882-7624", "researcher": {"href": "https://publications.scilifelab.se/researcher/0e701613f60249b793f2def737168a05.json"}}, {"family": "Guerreiro-Cacais", "given": "Andr\u00e9 Ortlieb", "initials": "AO", "orcid": "0000-0002-4561-2823", "researcher": {"href": "https://publications.scilifelab.se/researcher/9b824181455243b19f4aa145a4545870.json"}}, {"family": "Olsson", "given": "Tomas", "initials": "T"}], "type": "journal article", "published": "2026-01-22", "journal": {"title": "Cell", "issn": "1097-4172", "issn-l": "0092-8674", "volume": "189", "issue": "2", "pages": "585-602.e38"}, "abstract": "Epstein-Barr virus (EBV) infection constitutes a prerequisite for multiple sclerosis (MS) development, and cross-reactivity between EBV nuclear antigen 1 (EBNA1) and anoctamin-2 (ANO2) antibodies was previously demonstrated in persons with MS (pwMS). Here, we show that ANO2-specific CD4+ T cells are more frequent in pwMS. Immunization of SJL/J mice with ANO2 or EBNA1 led to cross-reactive CD4+ T cell and antibody responses. ANO2 pre-immunization led to exacerbated experimental autoimmune encephalomyelitis (EAE), an effect mediated by CD4+ T cells, as confirmed by adoptive transfer experiments. T cell clones with cross-reactivity to EBNA1 and ANO2 could be isolated from natalizumab-treated pwMS, and sequencing of EBNA1- and ANO2-specific T cell receptors (TCRs) revealed a significant repertoire overlap. We thus report the first mechanistic evidence that EBNA1 CD4+ T cells can target the MS autoantigen ANO2, thereby establishing a link between EBV infection and neuroinflammation.", "doi": "10.1016/j.cell.2025.12.032", "pmid": "41534529", "labels": {"Autoimmunity and Serology Profiling": "Service", "National Genomics Infrastructure": "Service", "NGI Stockholm (Genomics Production)": "Service", "NGI Short read": "Service"}, "xrefs": [{"db": "pii", "key": "S0092-8674(25)01481-3"}], "notes": [], "created": "2026-01-15T20:23:02.729Z", "modified": "2026-03-24T09:17:16.086Z"}, {"entity": "publication", "iuid": "c1686601bc6b4c808ba31fbb6c6d93d3", "links": {"self": {"href": "https://publications.scilifelab.se/publication/c1686601bc6b4c808ba31fbb6c6d93d3.json"}, "display": {"href": "https://publications.scilifelab.se/publication/c1686601bc6b4c808ba31fbb6c6d93d3"}}, "title": "A genetic-epigenetic interplay at 1q21.1 locus underlies CHD1L-mediated vulnerability to primary progressive multiple sclerosis.", "authors": [{"family": "Pahlevan Kakhki", "given": "Majid", "initials": "M", "orcid": "0000-0002-5407-3147", "researcher": {"href": "https://publications.scilifelab.se/researcher/5f376c85cfbe4711ae41d9ee5ade8f09.json"}}, {"family": "Giordano", "given": "Antonino", "initials": "A"}, {"family": "Starvaggi Cucuzza", "given": "Chiara", "initials": "C", "orcid": "0000-0002-9088-7658", "researcher": {"href": "https://publications.scilifelab.se/researcher/0ead2e8f98754d1586891eda5adb9e1a.json"}}, {"family": "Venkata S Badam", "given": "Tejaswi", "initials": "T"}, {"family": "Samudyata", "given": "Samudyata", "initials": "S"}, {"family": "Lem\u00e9e", "given": "Marianne Victoria", "initials": "MV", "orcid": "0000-0002-4897-0722", "researcher": {"href": "https://publications.scilifelab.se/researcher/361e3a91dc5245e587309759769414c8.json"}}, {"family": "Stridh", "given": "Pernilla", "initials": "P", "orcid": "0000-0003-4855-0039", "researcher": {"href": "https://publications.scilifelab.se/researcher/613e86be4685423093de57bb83be261b.json"}}, {"family": "Gkogka", "given": "Asimenia", "initials": "A"}, {"family": "Shchetynsky", "given": "Klementy", "initials": "K"}, {"family": "Harroud", "given": "Adil", "initials": "A", "orcid": "0000-0003-2616-7274", "researcher": {"href": "https://publications.scilifelab.se/researcher/91a769f610fb430e89258c1c30cbd23b.json"}}, {"family": "Gyllenberg", "given": "Alexandra", "initials": "A"}, {"family": "Liu", "given": "Yun", "initials": "Y"}, {"family": "Boddul", "given": "Sanjaykumar", "initials": "S"}, {"family": "James", "given": "Tojo", "initials": "T"}, {"family": "Sorosina", "given": "Melissa", "initials": "M"}, {"family": "Filippi", "given": "Massimo", "initials": "M", "orcid": "0000-0002-5485-0479", "researcher": {"href": "https://publications.scilifelab.se/researcher/8878f32c07334124b8e3bce42c94c076.json"}}, {"family": "Esposito", "given": "Federica", "initials": "F"}, {"family": "Wermeling", "given": "Fredrik", "initials": "F", "orcid": "0000-0001-9633-677X", "researcher": {"href": "https://publications.scilifelab.se/researcher/a34df8186ba24df3b14fe9743cf546b4.json"}}, {"family": "Gustafsson", "given": "Mika", "initials": "M", "orcid": "0000-0002-0048-4063", "researcher": {"href": "https://publications.scilifelab.se/researcher/466661ecb9274ecc8f1a832b95ef19b2.json"}}, {"family": "Casaccia", "given": "Patrizia", "initials": "P", "orcid": "0000-0002-4785-9264", "researcher": {"href": "https://publications.scilifelab.se/researcher/e62a7dde40bd454e9072ff43fff8a2ea.json"}}, {"family": "Hillert", "given": "Jan", "initials": "J"}, {"family": "Olsson", "given": "Tomas", "initials": "T"}, {"family": "Kockum", "given": "Ingrid", "initials": "I", "orcid": "0000-0002-0867-4726", "researcher": {"href": "https://publications.scilifelab.se/researcher/03ebcc6a01ef4d0db4e4673aff8de5d8.json"}}, {"family": "Sellgren", "given": "Carl M", "initials": "CM", "orcid": "0000-0001-9103-2785", "researcher": {"href": "https://publications.scilifelab.se/researcher/0c0740ddfd6d4c98988b2a19096a9814.json"}}, {"family": "Golzio", "given": "Christelle", "initials": "C"}, {"family": "Kular", "given": "Lara", "initials": "L", "orcid": "0000-0002-2907-6071", "researcher": {"href": "https://publications.scilifelab.se/researcher/09563004a20543dc934dd4d3b1ceebd7.json"}}, {"family": "Jagodic", "given": "Maja", "initials": "M", "orcid": "0000-0003-0756-889X", "researcher": {"href": "https://publications.scilifelab.se/researcher/b651ef39c6b0436992e2305f425eba72.json"}}], "type": "journal article", "published": "2024-07-30", "journal": {"title": "Nat Commun", "issn": "2041-1723", "volume": "15", "issue": "1", "pages": "6419", "issn-l": "2041-1723"}, "abstract": "Multiple Sclerosis (MS) is a heterogeneous inflammatory and neurodegenerative disease with an unpredictable course towards progressive disability. Treating progressive MS is challenging due to limited insights into the underlying mechanisms. We examined the molecular changes associated with primary progressive MS (PPMS) using a cross-tissue (blood and post-mortem brain) and multilayered data (genetic, epigenetic, transcriptomic) from independent cohorts. In PPMS, we found hypermethylation of the 1q21.1 locus, controlled by PPMS-specific genetic variations and influencing the expression of proximal genes (CHD1L, PRKAB2) in the brain. Evidence from reporter assay and CRISPR/dCas9 experiments supports a causal link between methylation and expression and correlation network analysis further implicates these genes in PPMS brain processes. Knock-down of CHD1L in human iPSC-derived neurons and knock-out of chd1l in zebrafish led to developmental and functional deficits of neurons. Thus, several lines of evidence suggest a distinct genetic-epigenetic-transcriptional interplay in the 1q21.1 locus potentially contributing to PPMS pathogenesis.", "doi": "10.1038/s41467-024-50794-z", "pmid": "39079955", "labels": {"NGI Short read": "Service", "NGI Stockholm (Genomics Production)": "Service", "National Genomics Infrastructure": "Service", "Bioinformatics Support for Computational Resources": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC11289459"}, {"db": "pii", "key": "10.1038/s41467-024-50794-z"}], "notes": [], "created": "2024-08-15T12:14:24.965Z", "modified": "2024-11-25T10:17:37.116Z"}, {"entity": "publication", "iuid": "552ba212eea247d8b241053070d1b005", "links": {"self": {"href": "https://publications.scilifelab.se/publication/552ba212eea247d8b241053070d1b005.json"}, "display": {"href": "https://publications.scilifelab.se/publication/552ba212eea247d8b241053070d1b005"}}, "title": "The astrocyte-produced growth factor HB-EGF limits autoimmune CNS pathology.", "authors": [{"family": "Linnerbauer", "given": "Mathias", "initials": "M", "orcid": "0000-0002-5528-5141", "researcher": {"href": "https://publications.scilifelab.se/researcher/27c1386bf72f4371acb131d333314da2.json"}}, {"family": "L\u00f6\u00dflein", "given": "Lena", "initials": "L", "orcid": "0000-0001-5705-9175", "researcher": {"href": "https://publications.scilifelab.se/researcher/0b3e8a2756064eb886c83c2f0d2fddef.json"}}, {"family": "Vandrey", "given": "Oliver", "initials": "O"}, {"family": "Peter", "given": "Anne", "initials": "A"}, {"family": "Han", "given": "Yanan", "initials": "Y"}, {"family": "Tsaktanis", "given": "Thanos", "initials": "T"}, {"family": "Wogram", "given": "Emile", "initials": "E"}, {"family": "Needhamsen", "given": "Maria", "initials": "M"}, {"family": "Kular", "given": "Lara", "initials": "L", "orcid": "0000-0002-2907-6071", "researcher": {"href": "https://publications.scilifelab.se/researcher/09563004a20543dc934dd4d3b1ceebd7.json"}}, {"family": "Nagel", "given": "Lisa", "initials": "L"}, {"family": "Zissler", "given": "Julia", "initials": "J"}, {"family": "Andert", "given": "Marie", "initials": "M", "orcid": "0009-0005-5440-8153", "researcher": {"href": "https://publications.scilifelab.se/researcher/bbedf36b1d214bd0b7e9f10a62465c33.json"}}, {"family": "Meszaros", "given": "Lisa", "initials": "L"}, {"family": "Hanspach", "given": "Jannis", "initials": "J"}, {"family": "Zuber", "given": "Finnja", "initials": "F"}, {"family": "Naumann", "given": "Ulrike J", "initials": "UJ"}, {"family": "Diebold", "given": "Martin", "initials": "M", "orcid": "0000-0001-9636-6936", "researcher": {"href": "https://publications.scilifelab.se/researcher/c78e07975fb042078617df5a4156c2cf.json"}}, {"family": "Wheeler", "given": "Michael A", "initials": "MA", "orcid": "0000-0002-0689-6384", "researcher": {"href": "https://publications.scilifelab.se/researcher/f271f2553bc54ad8851148c6516e99a3.json"}}, {"family": "Beyer", "given": "Tobias", "initials": "T"}, {"family": "Nirschl", "given": "Lucy", "initials": "L"}, {"family": "Cirac", "given": "Ana", "initials": "A"}, {"family": "Laun", "given": "Frederik B", "initials": "FB"}, {"family": "G\u00fcnther", "given": "Claudia", "initials": "C"}, {"family": "Winkler", "given": "J\u00fcrgen", "initials": "J"}, {"family": "B\u00e4uerle", "given": "Tobias", "initials": "T"}, {"family": "Jagodic", "given": "Maja", "initials": "M", "orcid": "0000-0003-0756-889X", "researcher": {"href": "https://publications.scilifelab.se/researcher/b651ef39c6b0436992e2305f425eba72.json"}}, {"family": "Hemmer", "given": "Bernhard", "initials": "B", "orcid": "0000-0001-5985-6784", "researcher": {"href": "https://publications.scilifelab.se/researcher/77d4cc3106604923a485c1bd9d5d1cb2.json"}}, {"family": "Prinz", "given": "Marco", "initials": "M", "orcid": "0000-0002-0349-1955", "researcher": {"href": "https://publications.scilifelab.se/researcher/df8ed6029343466694a94817f0f479e0.json"}}, {"family": "Quintana", "given": "Francisco J", "initials": "FJ"}, {"family": "Rothhammer", "given": "Veit", "initials": "V", "orcid": "0000-0003-0296-843X", "researcher": {"href": "https://publications.scilifelab.se/researcher/39f7424a439943dbaf449e579769506a.json"}}], "type": "journal article", "published": "2024-03-00", "journal": {"title": "Nat. Immunol.", "issn": "1529-2916", "volume": "25", "issue": "3", "pages": "432-447", "issn-l": "1529-2908"}, "abstract": "Central nervous system (CNS)-resident cells such as microglia, oligodendrocytes and astrocytes are gaining increasing attention in respect to their contribution to CNS pathologies including multiple sclerosis (MS). Several studies have demonstrated the involvement of pro-inflammatory glial subsets in the pathogenesis and propagation of inflammatory events in MS and its animal models. However, it has only recently become clear that the underlying heterogeneity of astrocytes and microglia can not only drive inflammation, but also lead to its resolution through direct and indirect mechanisms. Failure of these tissue-protective mechanisms may potentiate disease and increase the risk of conversion to progressive stages of MS, for which currently available therapies are limited. Using proteomic analyses of cerebrospinal fluid specimens from patients with MS in combination with experimental studies, we here identify Heparin-binding EGF-like growth factor (HB-EGF) as a central mediator of tissue-protective and anti-inflammatory effects important for the recovery from acute inflammatory lesions in CNS autoimmunity. Hypoxic conditions drive the rapid upregulation of HB-EGF by astrocytes during early CNS inflammation, while pro-inflammatory conditions suppress trophic HB-EGF signaling through epigenetic modifications. Finally, we demonstrate both anti-inflammatory and tissue-protective effects of HB-EGF in a broad variety of cell types in vitro and use intranasal administration of HB-EGF in acute and post-acute stages of autoimmune neuroinflammation to attenuate disease in a preclinical mouse model of MS. Altogether, we identify astrocyte-derived HB-EGF and its epigenetic regulation as a modulator of autoimmune CNS inflammation and potential therapeutic target in MS.", "doi": "10.1038/s41590-024-01756-6", "pmid": "38409259", "labels": {"Bioinformatics Support for Computational Resources": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC10907300"}, {"db": "pii", "key": "10.1038/s41590-024-01756-6"}], "notes": [], "created": "2024-11-25T10:19:50.350Z", "modified": "2025-02-28T14:15:42.709Z"}]}