“The epigenetic state of PRDM16-regulated enhancers in radial glia controls cortical neuron position”

For our August journal club we discussed a paper from 2018 from the lab of Dr. Corey Harwell, titled “The epigenetic state of PRDM16-regulated enhancers in radial glia controls cortical neuron position”. This well-rounded paper, which shows how a chromatin-modifying enzyme regulates a neurodevelopmental process, was a crash course for those of us in the lab who are novices in the field of epigenetics.

In the mammalian cerebral cortex, upper layer projection neurons develop in a process whereby radial glia (RG) give rise to intermediate progenitor (IP) cells that divide and then produce pairs of cortical neurons. Previous work showed that PRDM16, a chromatin-modifying enzyme, regulates neural stem cell maintenance and differentiation in the developing brain, and the Harwell group wanted to learn how this protein regulates gene expression in the developing cerebral cortex. Using beautiful immunofluorescent imaging and conditional knock-out (cKO) experiments, PRDM16 expression in RG is shown to promote production of IP cells and upper layer cortical neurons. RNA-seq and ChIP-seq experiments were performed and showed that PRDM16 regulates the transcriptional activation or silencing of genes important for the differentiation of RG into IP cells by epigenetic modification of enhancer regions. The strong activation of the E3 ubiquitin ligase Pdzrn3 in the cKO cortex suggests that it is normally silenced in RG by PRDM16 to promote upper layer cortical neuron migration. This is supported by the rescue of the upper layer cortical neuron defect by knocking down both Prdm16 and Pdzrn3. Finally, more beautiful imaging shows that the histone methyltransferase domain of PRDM16 is required for the silencing of Pdzrn3. Altogether, this paper does a nice job of showing how epigenetic regulation of gene transcription plays a role in setting up neuronal organization in the cortex. Thanks Harwell group for a great paper!