Cell type-specific functions of the PBAF chromatin-remodeling complex in neuronal diversification
Mutations in two highly related chromatin-remodeling complexes, BRG1/BRM-associated factor (BAF) and Polybromo-associated BAF (PBAF), cause various neurodevelopmental conditions. Although BAF activity is required at multiple steps of nervous system development, the specific neural functions of PBAF remain largely unexplored. Through an unbiased genetic screen in C. elegans, we identify here critical roles for PBAF in postmitotic neuronal identity. In nerve cord motor neurons, PBAF represses gene expression by antagonizing the terminal selector-type transcription factor UNC-3 (EBF1-4). In contrast, PBAF activates gene expression in caudal motor neurons. This dichotomy in PBAF function generates distinct motor neuron identities. PBAF disruption leads to locomotion defects. Genetic, genomic, and biochemical data suggest that the cell type-specific functions of PBAF in different motor neuron groups arise via its recruitment to specific gene loci by conserved transcription factors, such as MAB-9/TBX20. Altogether, our findings provide a conceptual framework to understand specific neuronal defects that arise in neurological conditions caused by mutations in broadly expressed chromatin-remodeling complexes.
Authors
- Honorine Destain (ORCID: https://orcid.org/0000-0002-6581-6372)
- Filipe Marques (ORCID: https://orcid.org/0000-0003-0757-2194)
- Laura D. Mathies (ORCID: https://orcid.org/0000-0002-2749-6531)
- Ian Q. Weigle (ORCID: https://orcid.org/0000-0002-1904-4367)
- Jayson J. Smith (ORCID: https://orcid.org/0000-0001-8525-7873)
- André EX Brown (ORCID: https://orcid.org/0000-0002-1324-8764)
- Priota Islam (ORCID: https://orcid.org/0000-0003-0512-0119)
- Paschalis Kratsios (ORCID: https://orcid.org/0000-0002-1363-9271)
- Natalie Grace Schulz (ORCID: https://orcid.org/0000-0001-6674-9688)
- Seth R. Taylor (ORCID: https://orcid.org/0000-0002-2227-1050)
- Anthony Osuma
- Jessica Mann (ORCID: https://orcid.org/0009-0009-3569-4309)
- Manasa Prahlad (ORCID: https://orcid.org/0000-0001-7849-9436)
- Yinan Li (ORCID: https://orcid.org/0000-0002-3244-1228)
Institutions
- Brigham Young University (US)
- Virginia Commonwealth University (US)
- University of Illinois Chicago (US)
- University of Chicago (US)
- MRC London Institute of Medical Sciences (GB)
- Imperial College London (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-14
- DOI
- https://doi.org/10.1038/s41467-025-67434-9
- Primary Topic
- Chromatin Remodeling and Cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- National Institutes of Health
- Office of Research Infrastructure Programs, National Institutes of Health