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Transcriptional enhancers in human neuronal differentiation provide clues to neuronal disorders
Karolinska Inst, Dept Med Huddinge MedH, Biosci & Nutr Unit, Stockholm, Sweden.;Chiba Univ, Inst Adv Acad Res, Chiba, Japan.;Chiba Univ, Grad Sch Med, Dept Artificial Intelligence Med, Chiba, Japan.;Osaka Univ, Premium Res Inst Human Metaverse Med WPI PRIMe, Suita, Osaka, Japan..
Karolinska Inst, Dept Med Huddinge MedH, Biosci & Nutr Unit, Stockholm, Sweden..
KTH, Centres, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0002-7212-813X
Karolinska Inst, Dept Med Huddinge MedH, Biosci & Nutr Unit, Stockholm, Sweden.;Univ Teramo, Dept Biosci & Technol Food Agr & Environm, Teramo, Italy..
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2025 (English)In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178Article in journal (Refereed) Epub ahead of print
Abstract [en]

Genome-wide association studies (GWASs) have identified thousands of variants associated with complex phenotypes, including neuropsychiatric disorders. To better understand their pathogenesis, it is necessary to identify the functional roles of these variants, which are largely located in non-coding DNA regions. Here, we employ a human mesencephalic neuronal cell differentiation model, LUHMES, with sensitive and high-resolution methods to discover enhancers (NET-CAGE), perform DNA conformation analysis (Capture Hi-C) to link enhancers to their target genes, and finally validate selected interactions. We expand the number of known enhancers active in differentiating human LUHMES neurons to 47,350, and find overlap with GWAS variants for Parkinson's disease and schizophrenia. Our findings reveal a fine-tuned regulation of human neuronal differentiation, even between adjacent developmental stages; provide a valuable resource for further studies on neuronal development, regulation, and disorders; and emphasize the importance of exploring the vast regulatory potential of non-coding DNA and enhancers.

Place, publisher, year, edition, pages
Springer Nature , 2025.
Keywords [en]
CAGE, Enhancer, Hi-C, LUHMES, Neuron
National Category
Medical Genetics and Genomics
Identifiers
URN: urn:nbn:se:kth:diva-360811DOI: 10.1038/s44319-025-00372-1ISI: 001420010600001PubMedID: 39948187Scopus ID: 2-s2.0-85217778039OAI: oai:DiVA.org:kth-360811DiVA, id: diva2:1941919
Note

QC 20250303

Available from: 2025-03-03 Created: 2025-03-03 Last updated: 2025-03-03Bibliographically approved

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Bachmann, Jörg A.Sahlén, Pelin

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