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PRDM16 regulates a temporal transcriptional program to promote progression of cortical neural progenitors

ABSTRACT: Radial glia (RG) in the neocortex sequentially generate distinct subtypes of projection neurons, accounting for the diversity and complex assembly of cortical neural circuits. Mechanisms that drive the rapid and precise temporal progression of RG are beginning to be elucidated. Here we reveal that the RG-specific transcriptional regulator PRDM16 promotes the transition of early to late phase of neurogenesis in the mouse neocortex. Loss of Prdm16 delays the timely progression of RG, leading to defective cortical laminar organization. Our genomic analyses demonstrate that PRDM16 regulates a subset of genes that are dynamically expressed between early and late neurogenesis. We show that PRDM16 suppresses target gene expression through limiting chromatin accessibility of permissive enhancers. We further confirm that critical target genes regulated by PRDM16 comprise neuronal specification genes, cell cycle regulators and molecules required for neuronal migration. These findings provide evidences to support that neural progenitors temporally shift gene expression program to achieve neural cell diversity.

ORGANISM(S): Mus musculus

PROVIDER: GSE162854 | GEO | 2021/03/03

REPOSITORIES: GEO

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Changes in DNA methylation upon gain and loss of Prdm16 function

Project description:Cortical neurogenesis requires the fine tuning of gene expression, modulated by genetic and epigenetic mechanisms during the entire process. Among the epigenetic factors expressed by the proliferative radial glia cells, Prdm16 has been shown to play a key role in cell proliferation. We found Prdm16 to be expressed exclusively by radial glia cells and to be rapidly turned off in newborn neurons. Predictably, Prdm16-null mice displayed a decrease in cortical thickness as a consequence of an impairment in self-renewal of radial glia cells. Conversely, Prdm16-overexpressing neural progenitors showed an increase in self-renewal activity and failed to complete differentiation. Lineage restriction in differentiating stem cells is achieved by chromatin modifications such as histone modifications and DNA methylation along the promoters of stemness-related genes. We found the expression of the DNA methyltransferase Dnmt3b to be inversely correlated to that of Prdm16. Loss and gain of Prdm16 function leaded to an up- and down-regulation of Dnmt3b, respectively. Functional analysis confirmed Prdm16 competence to repress Dnmt3b expression. Finally, IUE of Prdm16 together with Dnmt3b rescued the increase in radial glia cells self-renewal observed with Prdm16 alone. Thus, Prdm16 may play a crucial role in ensuring neural progenitor self-renewal, mainly through the maintenance of the unmethylated state of stemness-related genes.

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