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

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.

Influence without Presence: PRDM16 Casts Destiny

“…These distal-acting elements are often enriched with distinct histone modifications, such as H3K4me and H3K27ac, and binding motifs for transcriptional co-factors that are important for cell fate determination and differentiation (Creyghton et al, 2010). Baizabal et al (2018) show that PRDM16-binding sites are highly enriched with active enhancer histone modification, H3K27ac, and modestly associated with the poised and active enhancer marker H3K4me, suggesting that PRDM16 primarily binds to active enhancers. Furthermore, the majority of PRDM16-bound genomic regions are active enhancers only during cortical development.…”

“…Similar to transcription profile, epigenetic modification patterns change as NSPCs differentiate into different cell types and are under tight temporal and spatial regulation. In this issue of Neuron, Baizabal et al (2018) demonstrate how PRDM16 regulates upper-layer neurogenesis by embedding epigenetic information in RGCs to convey controls on the behavior of their progeny, in which PRDM16 is no longer present.…”

“…PRDM16 also interacts with a number of transcriptional regulators to play a critical role in cell fate determination such as adipocyte specification. In the developing cerebral cortex, expression of Prdm16 is highly enriched in the VZ and diminished as RGCs progress through IPCs to differentiating neurons (Shimada et al, 2017;Baizabal et al, 2018). Previous studies show that PRDM16 is required for adult neural stem cell maintenance and ependymal cell differentiation (Shimada et al, 2017).…”

“…In order to study the function of PRDM16 in the developing cerebral cortex, Baizabal et al (2018) first determined that PRDM16 is mainly expressed in PAX6 + RGCs including PAX6 + /TBR2 + RGCs that undergo transitioning to IPCs in the VZ, but not in PAX6 À /TBR2 + IPCs and neurons. They constructed Prdm16 conditional knockouts (cKO) using the Emx1 Cre transgenic mouse lines.…”

“…Based on analysis from RNA-seq, ChIP-seq of PRDM16, and histone modifications, together with in situ expression analysis and in vivo functional analysis comparing WT and cKO cortex, Baizabal et al (2018) identified PDZRN3, an E3 ubiquitin ligase, as a direct target repressed by PRDM16. In the embryonic cortex, the expression level of Pdzrn3 is relatively low in the VZ and SVZ, and later reaches the peak in the IZ, then drops down in the cortical plate.…”