We have previously identified a subset of transcriptional enhancers in neural stem cells that determine the final position of projection neurons in the cerebral cortex (Baizabal et al., Neuron 2018). These enhancer regions are regulated by the histone methyl-transferase PRDM16 during embryonic neurogenesis. Prdm16 is expressed in neural stem cells and silenced in cortical neurons. In the absence of PRDM16 activity in neural stem cells, newborn neurons do not reach their final position in the brain and remain in ectopic locations, thereby affecting the layered-organization of the cortex and the formation of neuronal circuits.
Our results provide mechanistic insights into two fundamental aspects of cortical development:
1) The complex features of the mature cerebral cortex are directly encoded in the epigenome of neural stem cells.
2) Transient epigenetic regulation in neural stem cells exerts a long-lasting impact in their neuronal and glial progeny.
To further explore these ideas, we are currently working on several experimental approaches to test whether a code of histone methylations/acetylations within the regulatory genome of neural stem cells is critical to control later stages of neurogenesis. We are also using CRISPR tools in vivo to identify chromatin-modifying enzymes and transcriptional enhancers with a critical role in cortical development and human neurodevelopmental disorders. Furthermore, we are studying the mechanisms by which epigenetic dysregulation in mature cortical neurons might trigger cellular senescence and neurodegeneration.
