Time series modeling of cell cycle exit identifies Brd4 dependent regulation of cerebellar neurogenesis

Clara Penas, Marie E. Maloof, Vasileios Stathias, Jun Long, Sze Kiat Tan, Jose Mier, Yin Fang, Camilo Valdes, Jezabel Rodriguez-Blanco, Cheng Ming Chiang, David J. Robbins, Daniel J. Liebl, Jae K. Lee, Mary E. Hatten, Jennifer Clarke, Nagi G. Ayad

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Cerebellar neuronal progenitors undergo a series of divisions before irreversibly exiting the cell cycle and differentiating into neurons. Dysfunction of this process underlies many neurological diseases including ataxia and the most common pediatric brain tumor, medulloblastoma. To better define the pathways controlling the most abundant neuronal cells in the mammalian cerebellum, cerebellar granule cell progenitors (GCPs), we performed RNA-sequencing of GCPs exiting the cell cycle. Time-series modeling of GCP cell cycle exit identified downregulation of activity of the epigenetic reader protein Brd4. Brd4 binding to the Gli1 locus is controlled by Casein Kinase 1δ (CK1 δ)-dependent phosphorylation during GCP proliferation, and decreases during GCP cell cycle exit. Importantly, conditional deletion of Brd4 in vivo in the developing cerebellum induces cerebellar morphological deficits and ataxia. These studies define an essential role for Brd4 in cerebellar granule cell neurogenesis and are critical for designing clinical trials utilizing Brd4 inhibitors in neurological indications.

Original languageEnglish (US)
Article number3028
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Penas, C., Maloof, M. E., Stathias, V., Long, J., Tan, S. K., Mier, J., Fang, Y., Valdes, C., Rodriguez-Blanco, J., Chiang, C. M., Robbins, D. J., Liebl, D. J., Lee, J. K., Hatten, M. E., Clarke, J., & Ayad, N. G. (2019). Time series modeling of cell cycle exit identifies Brd4 dependent regulation of cerebellar neurogenesis. Nature communications, 10(1), [3028]. https://doi.org/10.1038/s41467-019-10799-5