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Decoding gene regulation in the fly brain
Open accessPreprint — published as 10.1038/s41586-021-04262-z · Paper page
Abstract
Summary: The Drosophila brain is a work horse in neuroscience. Single-cell transcriptome analysis 1–5, 3D morphological classification 6 , and detailed EM mapping of the connectome 7–10 have revealed an immense diversity of neuronal and glial cell types that underlie the wide array of functional and behavioral traits in the fruit fly. The identities of these cell types are controlled by – still unknown – gene regulatory networks (GRNs), involving combinations of transcription factors that bind to genomic enhancers to regulate their target genes. To characterize the GRN for each cell type in the Drosophila brain, we profiled chromatin accessibility of 240,919 single cells spanning nine developmental timepoints, and integrated this data with single-cell transcriptomes. We identify more than 95,000 regulatory regions that are used in different neuronal cell types, of which around 70,000 are linked to specific developmental trajectories, involving neurogenesis, reprogramming and maturation. For 40 cell types, their uniquely accessible regions could be associated with their expressed transcription factors and downstream target genes, through a combination of motif discovery, network inference techniques, and deep learning. We illustrate how these “enhancer-GRNs” can be used to reveal enhancer architectures leading to a better understanding of neuronal regulatory diversity. Finally, our atlas of regulatory elements can be used to design genetic driver lines for specific cell types at specific timepoints, facilitating the characterization of brain cell types and the manipulation of brain function.
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“methods for inferring enhancer-driven GRNs (eGRNs) that integrate enhancer sequence, chromatin accessibility and gene expression22–24 found that the accuracy to predict active enhancers increases by ~10% compared to using accessibility alone25.”
From Enhancer grammar of liver cell types and hepatocyte zonation states (2022) · cites this paper as [25]
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Bravo González-Blas, C., De Winter, S., Hulselmans, G., Hecker, N., Matetovici, I., Christiaens, V., Poovathingal, S., Wouters, J., Aibar, S., & Aerts, S. (2023) · Nature Methods · doi:10.1038/s41592-023-01938-4 · Cited by 778
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Cell-type-directed design of synthetic enhancers
Taskiran, I. I., Spanier, K. I., Dickmänken, H., Kempynck, N., Pančíková, A., Ekşi, E. C., Hulselmans, G., Ismail, J. N., Theunis, K., Vandepoel, R., et al. (2024) · Nature · doi:10.1038/s41586-023-06936-2 · Cited by 175
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Metadata
- Authors
- Janssens, J., Aibar, S., Taskiran, I. I., Ismail, J. N., Spanier, K. I., Bravo González-Blas, C., Quan, X. J., Papasokrati, D., Hulselmans, G., Makhzami, S., Waegeneer, M. D., Christiaens, V., & Aerts, S.
- Affiliations
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- Corresponding author
- Aerts, Stein
- ORCID
- Venue
- Nature
- Publisher
- openRxiv
- Published
- 2021-08-12
- Volume
- 601
- Issue
- 7894
- Pages
- 630-636
- ISSN
- 0028-0836 (ISSN-L)
- OpenAlex
- W4205345182
- Cited by
- 170
- References
- 143
- Citations by year
- 2026: 22 · 2025: 36 · 2024: 35 · 2023: 40 · 2022: 35 · 2021: 1
- FWCI
- 12.15
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Lirias (submittedVersion, other-oa)
- Funders
- Wellcome Trust (207467/Z/17/Z)
- Medical Research Council (MR/L018802/1, MR/L018802/2)
- Biotechnology and Biological Sciences Research Council (BB/W001004/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Keywords
- Drosophila brain, gene regulatory networks, enhancers, chromatin accessibility, single-cell transcriptomics, transcription factors, transcription factor binding sites, neuronal cell types, neurogenesis, developmental trajectories
- MeSH terms
- Animals, Brain, Drosophila, Gene Expression Regulation, Transcription Factors, Gene Expression Regulation, Developmental, Gene Regulatory Networks
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