The evolution of gene regulation in mammalian cerebellum development
Gene regulatory changes are considered major drivers of evolutionary innovations, including the cerebellum's expansion during human evolution, yet they remain largely unexplored. In this study, we combined single-nucleus measurements of gene expression and chromatin accessibility from six mammals (human, bonobo, macaque, marmoset, mouse, and opossum) to uncover conserved and diverged regulatory networks in cerebellum development. We identified core regulators of cell identity and developed sequence-based models that revealed conserved regulatory codes. By predicting chromatin accessibility across 240 mammalian species, we reconstructed the evolutionary histories of human cis-regulatory elements, identifying sets associated with positive selection and gene expression changes, including the recent gain of <i>THRB</i> expression in cerebellar progenitor cells. Collectively, our work reveals the shared and mammalian lineage-specific regulatory programs governing cerebellum development.
Authors
- Lena M. Kutscher (ORCID: https://orcid.org/0000-0002-1130-4582)
- Konstantin Okonechnikov (ORCID: https://orcid.org/0000-0002-3409-2340)
- Ioannis Sarropoulos (ORCID: https://orcid.org/0000-0002-2242-0562)
- Piyush Joshi (ORCID: https://orcid.org/0000-0002-5631-336X)
- Charis Drummer (ORCID: https://orcid.org/0000-0002-1382-2228)
- Evgeny V. Leushkin (ORCID: https://orcid.org/0000-0001-5959-6943)
- Nikolai Hecker (ORCID: https://orcid.org/0000-0003-1693-4257)
- A.J. Stein
- Ibrahim Ihsan Taskiran (ORCID: https://orcid.org/0000-0002-5077-5264)
- Mari Sepp (ORCID: https://orcid.org/0000-0003-1733-8385)
- Sophie Mißbach
- Kevin Leiss (ORCID: https://orcid.org/0000-0002-5955-6076)
- Nils Trost (ORCID: https://orcid.org/0000-0002-5171-018X)
- Robert Frömel (ORCID: https://orcid.org/0000-0002-0438-8677)
- Miklós Palkovits (ORCID: https://orcid.org/0000-0003-0578-0387)
- Henrik Kaessmann (ORCID: https://orcid.org/0000-0001-7563-839X)
- Julia Schmidt (ORCID: https://orcid.org/0000-0002-4617-3463)
- Frederik Arnskötter
- C. Schneider
- Margarida Cardoso-Moreira
- Philipp S. L. Schäfer
- Rüdiger Behr
Institutions
- Semmelweis University (HU)
- Okinawa Institute of Science and Technology Graduate University (JP)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- The Francis Crick Institute (GB)
- German Primate Center (DE)
- University Hospital Heidelberg (DE)
- VIB-KU Leuven Center for Cancer Biology (BE)
- National Center for Tumor Diseases (DE)
- Hopp Children's Cancer Center Heidelberg (DE)
- Max Planck Institute for Evolutionary Anthropology (DE)
- DKFZ-ZMBH Alliance (DE)
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Newcastle University (GB)
- KU Leuven (BE)
Publication Details
- Journal
- Science
- Published
- 2026-01-29
- DOI
- https://doi.org/10.1126/science.adw9154
- Citations
- 2
- Primary Topic
- Developmental Biology and Gene Regulation
- Type
- article
- Field-Weighted Citation Impact
- 44.47