{"entity": "researcher", "timestamp": "2026-06-15T16:51:38.673Z", "family": "Pahlevan Kakhki", "given": "Majid", "initials": "M", "orcid": "0000-0002-5407-3147", "affiliations": ["Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden."], "links": {"self": {"href": "https://publications.scilifelab.se/researcher/5f376c85cfbe4711ae41d9ee5ade8f09.json"}, "display": {"href": "https://publications.scilifelab.se/researcher/5f376c85cfbe4711ae41d9ee5ade8f09"}}, "publications": [{"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": "e962bd7ef8824c55975d40adb2d41799", "links": {"self": {"href": "https://publications.scilifelab.se/publication/e962bd7ef8824c55975d40adb2d41799.json"}, "display": {"href": "https://publications.scilifelab.se/publication/e962bd7ef8824c55975d40adb2d41799"}}, "title": "Oligodendroglia as functional effectors of Multiple Sclerosis risk variants", "authors": [{"family": "Carlstr\u00f6m", "given": "Karl E", "initials": "KE", "orcid": "0000-0002-3001-2403", "researcher": {"href": "https://publications.scilifelab.se/researcher/3aa5f65acad34b5790a2b9f607521825.json"}}, {"family": "Agirre", "given": "Eneritz", "initials": "E"}, {"family": "Sun", "given": "Ting", "initials": "T", "orcid": "0000-0002-7104-7215", "researcher": {"href": "https://publications.scilifelab.se/researcher/521fca43267242fca06da0f5fc823e6a.json"}}, {"family": "Dumral", "given": "\u00d6zge", "initials": "\u00d6"}, {"family": "Kabbe", "given": "Mukund", "initials": "M"}, {"family": "Mahmud", "given": "Neemat", "initials": "N"}, {"family": "Kit Lor", "given": "Yuk", "initials": "Y"}, {"family": "Pahlevan Kakhki", "given": "Majid", "initials": "M", "orcid": "0000-0002-5407-3147", "researcher": {"href": "https://publications.scilifelab.se/researcher/5f376c85cfbe4711ae41d9ee5ade8f09.json"}}, {"family": "Khademi", "given": "Mohsen", "initials": "M"}, {"family": "Jagodic", "given": "Maja", "initials": "M"}, {"family": "Goldman", "given": "Steve A", "initials": "SA", "orcid": "0000-0002-5498-4303", "researcher": {"href": "https://publications.scilifelab.se/researcher/7a78fe500aa54369b3716c70792dee90.json"}}, {"family": "Castelo-Branco", "given": "Gon\u00e7alo", "initials": "G", "orcid": "0000-0003-2247-9393", "researcher": {"href": "https://publications.scilifelab.se/researcher/10b1a8fb48114340b8e390ca1f9e3321.json"}}], "type": "posted-content", "published": "2025-11-12", "journal": {"title": "biorxiv", "issn": null, "issn-l": null, "volume": null, "issue": null, "pages": null}, "abstract": null, "doi": "10.1101/2025.11.11.687640", "pmid": null, "labels": {"CRISPR Functional Genomics": "Service", "National Genomics Infrastructure": "Service", "NGI Stockholm (Genomics Production)": "Service", "NGI Short read": "Service"}, "xrefs": [], "notes": [], "created": "2025-11-19T09:35:53.525Z", "modified": "2025-12-18T18:35:03.301Z"}, {"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"}]}