PreprintCited by 173Genomics and Chromatin DynamicsSingle-cell and spatial transcriptomicsGene Regulatory Network Analysis

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Decoding gene regulation in the fly brain

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Janssens, Jasper, Aibar, Sara, Taskiran, Ibrahim Ihsan, Ismail, Joy N., Spanier, Katina I., Bravo González-Blas, Carmen, Quan, Xiao Jiang, Papasokrati, Dafni, Hulselmans, Gert, Makhzami, Samira, Waegeneer, Maxime De, Christiaens, Valerie, Aerts, Stein·2021·Nature

DOI 10.1101/2021.08.11.454937

Preprint — published as 10.1038/s41586-021-04262-z · Paper page

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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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10.1093/bioinformatics/btx194. · DOI · Paper page
10.1101/2020.04.28.066498 · DOI
Shrikumar, A. , Greenside, P. & Kundaje, A . Learning Important Features Through Propagating Activation Differences. arXiv:1704.02685 [cs] (2019). · arXiv

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Fly Cell Atlas: A single-nucleus transcriptomic atlas of the adult fruit fly
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SCENIC+: single-cell multiomic inference of enhancers and gene regulatory networks
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Cell-type-directed design of synthetic enhancers
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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: Janssens, Jasper
Aibar, Sara
Taskiran, Ibrahim Ihsan
Ismail, Joy N.
Spanier, Katina I.
Bravo González-Blas, Carmen
Quan, Xiao Jiang
Papasokrati, Dafni
Hulselmans, Gert
Makhzami, Samira
Waegeneer, Maxime De
Christiaens, Valerie
Aerts, Stein
Venue: Nature
Publisher: openRxiv
Published: 2021-08-12
Volume: 601
Issue: 7894
Pages: 630-636
ISSN: 0028-0836 (ISSN-L)
DOI: 10.1101/2021.08.11.454937
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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