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 and Nagi G. Ayad ()
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Clara Penas: University of Miami Miller School of Medicine
Marie E. Maloof: University of Miami Miller School of Medicine
Vasileios Stathias: University of Miami Miller School of Medicine
Jun Long: University of Miami Miller School of Medicine
Sze Kiat Tan: University of Miami Miller School of Medicine
Jose Mier: University of Miami Miller School of Medicine
Yin Fang: The Rockefeller University
Camilo Valdes: Florida International University
Jezabel Rodriguez-Blanco: University of Miami Miller School of Medicine
Cheng-Ming Chiang: University of Texas Southwestern Medical Center
David J. Robbins: University of Miami Miller School of Medicine
Daniel J. Liebl: University of Miami Miller School of Medicine
Jae K. Lee: University of Miami Miller School of Medicine
Mary E. Hatten: The Rockefeller University
Jennifer Clarke: University of Nebraska
Nagi G. Ayad: University of Miami Miller School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10799-5

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