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Neuron. 2018 Jun 6;98(5):945-962.e8. doi: 10.1016/j.neuron.2018.04.033. Epub 2018 May 17.

The Epigenetic State of PRDM16-Regulated Enhancers in Radial Glia Controls Cortical Neuron Position.

Author information

1
Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: manuelbaizabal2018@gmail.com.
2
Bioinformatics Core, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Harvard Medical School, Boston, MA 02115, USA.
3
Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
4
Division of Genetics and Genomics, Manton Center for Orphan Disease and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
5
Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: corey_harwell@hms.harvard.edu.

Abstract

The epigenetic landscape is dynamically remodeled during neurogenesis. However, it is not understood how chromatin modifications in neural stem cells instruct the formation of complex structures in the brain. We report that the histone methyltransferase PRDM16 is required in radial glia to regulate lineage-autonomous and stage-specific gene expression programs that control number and position of upper layer cortical projection neurons. PRDM16 regulates the epigenetic state of transcriptional enhancers to activate genes involved in intermediate progenitor cell production and repress genes involved in cell migration. The histone methyltransferase domain of PRDM16 is necessary in radial glia to promote cortical neuron migration through transcriptional silencing. We show that repression of the gene encoding the E3 ubiquitin ligase PDZRN3 by PRDM16 determines the position of upper layer neurons. These findings provide insights into how epigenetic control of transcriptional enhancers in radial glial determines the organization of the mammalian cerebral cortex.

KEYWORDS:

PDZRN3; PRDM16; cerebral cortex; enhancer; epigenetic; migration; neural stem cell; neurogenesis; radial glia

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