While epigenetic studies have shown us that the past sculpts the future, the mechanisms have remained a cognitive conundrum, particularly when it comes the developing brain. Thankfully, a stimulating new study has come forth to show how early-life brain activity flips a switch that establishes cell-type specific enhancers for life.
To prime our brains with this insight, the lab of Michael Greenberg (Harvard Medical School) looked at the developmental transition of postnatal mouse neurons using two different neuronal subtypes at three different time points. Their goal was to characterize the formation of cell-type-specific enhancers modulated by early-life synaptic activity. This clever team used a variety of techniques to investigate the molecular changes occurring as neurons mature.
Here’s how the story matured:
- Early on, embryonic genes are downregulated while synaptic genes are upregulated, with fewer changes at later time points detected via RNA-seq
- At enhancers associated with upregulated genes, there are changes in accessibility detected via ATAC-seq and enhancer-associated H3K27ac via ChIP-seq
- DNA methylation is also acquired to promote repression of embryonic genes, as detected using WGBS, which helps with the switch to new enhancers
- Transcription factors are differentially expressed and appear to mediate this maturational switch
- AP1 family transcription factors, such as FOS, are activity-regulated and by using CUT&RUN, they were able to show enriched FOS binding at these newly formed enhancers following induced synapse activation at glutamate receptors
- Finally, overexpression of KIR2.1 to reduce neuron activity results in lower activity-regulated gene expression
Altogether, this work suggests that activity-induced transcription factors contribute to enhancer activation and ultimately gene expression of genes important for brain maturation, which remain active throughout adulthood. These findings also contribute to our understanding of Autism Spectrum Disorders and Schizophrenia as the stages of neurodevelopment studied are often deregulated in these disorders.
Enhance your own understanding at Neuron, September 2020.
If you’d like to read more about the ATAC-Seq method, please visit this great blog article from our friends at Active Motif – Complete Guide to Understanding and Using ATAC-Seq.