Transcriptional enhancers in human neuronal differentiation provide clues to neuronal disorders
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.
Authors
- Mariangela Pucci (ORCID: https://orcid.org/0000-0003-4657-6075)
- Andrea Coschiera (ORCID: https://orcid.org/0000-0003-0602-2473)
- Jörg A. Bachmann (ORCID: https://orcid.org/0000-0002-7212-813X)
- Masahito Yoshihara (ORCID: https://orcid.org/0000-0002-8915-9282)
- Eeva‐Mari Jouhilahti (ORCID: https://orcid.org/0000-0003-2879-7659)
- Peter Swoboda (ORCID: https://orcid.org/0000-0001-6416-8572)
- Yasuhiro Murakawa (ORCID: https://orcid.org/0000-0002-5415-1352)
- Jere Weltner
- Pelin Sahlén (ORCID: https://orcid.org/0000-0001-6943-9618)
- Shruti Bhagat (ORCID: https://orcid.org/0000-0003-1403-1783)
- Juha Kere (ORCID: https://orcid.org/0000-0003-1974-0271)
- Haonan Li (ORCID: https://orcid.org/0000-0002-0501-4394)
Institutions
- University of Teramo (IT)
- University of Helsinki (FI)
- Chiba University (JP)
- Kyoto University (JP)
- Science for Life Laboratory (SE)
- Karolinska Institutet (SE)
- IFOM (IT)
- RIKEN Center for Integrative Medical Sciences (JP)
- Folkhälsans Forskningscentrum (FI)
- KTH Royal Institute of Technology (SE)
- The University of Osaka (JP)
Publication Details
- Journal
- EMBO Reports
- Published
- 2025-02-13
- DOI
- https://doi.org/10.1038/s44319-025-00372-1
- Citations
- 5
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 4.03
Funders
- Torsten Söderbergs Stiftelse
- Carl Tryggers Stiftelse för Vetenskaplig Forskning
- Jane ja Aatos Erkon Säätiö
- Karolinska Institutet
- Stiftelsen Olle Engkvist Byggmästare
- Vetenskapsrådet
- China Scholarship Council
- Åhlén-stiftelsen
- Sigrid Juséliuksen Säätiö
- Swedish Brain Power
- Japan Society for the Promotion of Science
- Uppsala Multidisciplinary Center for Advanced Computational Science