Upcycling is the latest of many green crazes where people keep hold of old furniture and instead of throwing it away, they repurpose it to give new life. It seems that the brain might be doing the same for methylation. It’s been a long held belief that DNA methylation is fixed in differentiated cells, yet there is plenty of methylation remodelling happening in cells of the brain, suggesting that DNA methylation may get repurposed in these differentiated cells. In order to understand what is really going on the lab of Hongjun Song at Johns Hopkins have just provided extensive characterization of DNA demethylation in post-mitotic neurons of the brain, which, as it turns out, allows neurons to adapt to communications sent between them.
Alterations to DNA methylation are naturally associated with changing the heritable properties of a sequence, but it now seems the brain has hijacked epigenetic machinery for its own purpose. DNA demethylation is an active process enabled by the TET enzyme family, which is much more dynamic than the passive removal of methylation through lack of maintenance across replication. The groups findings regarding the role of active demethylation in neurons centres on the way neurons communicate to each other: via junctions known as synapses that are a biochemical way of transmitting electrical signals to a neighbouring neuron.
The authors analyzed cultured primary hippocampal neurons from mouse embryos and found:
- Synaptic activity regulates Tet3.
- Knockdown of Tet (and related pathways) increases the synaptic transmission of glutamate, a neurotransmitter important for neuronal activation.
- Overexpressing the Tet3 or Tet1 catalytic domain decreases glutamatergic transmission.
- Tet3 enables a rapid directional scaling of glutamate receptors (GluR1) on a neuron’s surface.
- RNA-seq showed Tet3 regulates the DNA methylation and thus the expression of genes related to synaptic activity.
This type of response is known as meta-plasticity and is an interesting phenomenon where a neuron’s past experience determines its ability to undergo future relations, making it an essential component to learning and memory. This research also represents the first instance of active demethylation regulating synaptic transmission. Thus, it appears that Tet3 serves as a dynamic mechanism for a neuron’s epigenome to fine tune its response and stay stable while dealing with the signals coming directly or indirectly from any of 100 billion chatty neighbours.
Go check out how neurons upcycle the epigneome in Nature Neuroscience, March 2015.