Evaluating methods for the prediction of cell-type-specific enhancers in the mammalian cortex.

Journal: Cell genomics
Published Date: May 21, 2025

Abstract

Identifying cell-type-specific enhancers is critical for developing genetic tools to study the mammalian brain. We organized the "Brain Initiative Cell Census Network (BICCN) Challenge: Predicting Functional Cell Type-Specific Enhancers from Cross-Species Multi-Omics" to evaluate machine learning and feature-based methods for nominating enhancer sequences targeting mouse cortical cell types. Methods were assessed using in vivo data from hundreds of adeno-associated virus (AAV)-packaged, retro-orbitally delivered enhancers. Open chromatin was the strongest predictor of functional enhancers, while sequence models improved prediction of non-functional enhancers and identified cell-type-specific transcription factor codes to inform in silico enhancer design. This challenge establishes a benchmark for enhancer prioritization and highlights computational and molecular features critical for identifying functional cortical enhancers, advancing efforts to map and manipulate gene regulation in the mammalian cortex.

Authors

  • Nelson J Johansen
    Allen Institute for Brain Science, Seattle, WA 98109, USA.
  • Niklas Kempynck
    Laboratory of Computational Biology, VIB Center for AI & Computational Biology (VIB.AI), Leuven, Belgium.
  • Nathan R Zemke
    Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Saroja Somasundaram
    Allen Institute for Brain Science, Seattle, WA 98109, USA.
  • Seppe De Winter
    VIB Center for AI & Computational Biology, VIB-KU Leuven Center for Brain and Disease Research & KU Leuven Department of Human Genetics, Leuven, Belgium.
  • Marcus Hooper
    Allen Institute for Brain Science, Seattle, WA 98109, USA.
  • Deepanjali Dwivedi
    Allen Institute for Brain Science, Seattle, WA 98109, USA.
  • Ruchi Lohia
    Physiology Department and Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada.
  • Fabien Wehbe
    Maisonneuve-Rosemont Hospital Research Center (CRHMR), Department of Medicine, University of Montreal, Quebec H1T 2M4, Canada.
  • Bocheng Li
    School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
  • Darina Abaffyová
    VIB Center for AI & Computational Biology, VIB-KU Leuven Center for Brain and Disease Research & KU Leuven Department of Human Genetics, Leuven, Belgium.
  • Ethan J Armand
    Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA 92093, USA.
  • Julie De Man
    VIB Center for AI & Computational Biology, VIB-KU Leuven Center for Brain and Disease Research & KU Leuven Department of Human Genetics, Leuven, Belgium.
  • Eren Can Ekşi
    Laboratory of Computational Biology, VIB Center for AI & Computational Biology (VIB.AI), Leuven, Belgium.
  • Nikolai Hecker
    VIB Center for AI & Computational Biology, VIB-KU Leuven Center for Brain and Disease Research & KU Leuven Department of Human Genetics, Leuven, Belgium.
  • Gert Hulselmans
    VIB-KU Leuven Center for Brain and Disease Research, 3000 Leuven, Belgium.
  • Vasilis Konstantakos
    VIB Center for AI & Computational Biology, VIB-KU Leuven Center for Brain and Disease Research & KU Leuven Department of Human Genetics, Leuven, Belgium.
  • David Mauduit
    VIB-KU Leuven Center for Brain and Disease Research, 3000 Leuven, Belgium.
  • John K Mich
    Allen Institute for Brain Science, Seattle, WA 98109, USA.
  • Gabriele Partel
    Centre for Image Analysis, Uppsala University, Uppsala, 75124, Sweden.
  • Tanya L Daigle
    Allen Institute for Brain Science, 615 Westlake Avenue N, Seattle, Washington 98109, USA.
  • Boaz P Levi
    Allen Institute for Brain Science, Seattle, WA 98109, USA.
  • Kai Zhang
    Anhui Province Key Laboratory of Respiratory Tumor and Infectious Disease, First Affiliated Hospital of Bengbu Medical University, Bengbu, China.
  • Yoshiaki Tanaka
    Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
  • Jesse Gillis
    Cold Spring Harbor Laboratory, Stanley Institute for Cognitive Genomics, Cold Spring Harbor, NY 11724, USA.
  • Jonathan T Ting
    Allen Institute for Brain Science, Seattle, WA 98109, USA; Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195, USA.
  • Yoav Ben-Simon
    Allen Institute for Brain Science, Seattle, WA 98109, USA.
  • Jeremy Miller
    Allen Institute for Brain Science, Seattle, WA 98109, USA.
  • Joseph R Ecker
    Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA.
  • Bing Ren
    Ludwig Institute for Cancer Research, La Jolla, CA, 92093, USA.
  • Stein Aerts
    VIB-KU Leuven Center for Brain and Disease Research, 3000 Leuven, Belgium.
  • Ed S Lein
    Allen Institute for Brain Science, Seattle, Washington, 98103, USA.
  • Bosiljka Tasic
    Allen Institute for Brain Science, Seattle, WA 98109, USA.
  • Trygve E Bakken
    Allen Institute for Brain Science, Seattle, WA 98109, USA. Electronic address: trygveb@alleninstitute.org.

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