It takes real restraint to prevent a routine hedge trim from turning into a horticultural horror show; and like an overzealous landscaper, new research shows that TET2 may be mowing down the methylome in Parkinson’s Disease (PD) neurons.
The cognitive and motor symptoms of PD are caused by the degeneration of dopamine-producing neurons in the brain, and although we know that DNA methylation is like fertilizer to healthy neurons, we don’t understand how PD neurons get put out to grass.
A new study from the lab of Viviane Labrie (Michigan State University, USA) decided to root out the problem using post-mortem brain samples from PD patients. Instead of beating around the bush and sequencing the entire methylome, they used bisfulite padlock probe sequencing to examine the methylation status of brain-specific enhancers, which are likely targets of dysregulation.
The talented team used their in-depth approach on neurons from the prefrontal cortex, that were separated by flow cytometry, and found that:
- Almost 2,000 cytosines are differentially methylated in PD compared to control neurons
- These sites tend to be hypermethylated and occur more often in the CpH context than CpG context
- Downstream target genes of differentially methylated enhancers, as determined by Hi-C contact maps, include known PD risk genes and the TET2 DNA demethylase
Next, they used hydroxymethylated DNA immunoprecipitation (hMeDIP-seq) to weed out the effects of TET2 dysfunction and found that many of the PD-associated enhancers are actually hypomethylated! Since TET2 transcript levels are also higher in PD brains, the savvy scientists laid the groundwork for the role of TET2 in disease progression. They found that:
- There is a region of hypermethylation at an intragenic enhancer in TET2, and hypomethylation of the TET2 promoter which both increases in severity along with PD disease progression
- Depleting TET2 in dopaminergic neurons with siRNA has the reciprocal effect to what’s seen in PD neurons
- Tet2 knockout mice injected with lipopolysaccharide, which causes PD-like neuron degeneration in wildtype animals, are protected from neuronal loss and motor deficits
The genes that are most impacted in the mouse model are related to immune response, and the study’s senior author Dr. Labrie says, “Temporarily reducing TET2 activity could be one way to interfere with multiple contributors to the disease, especially inflammatory events, and protect the brain from loss of dopamine-producing cells. More work is needed before a TET2-based intervention can be developed, but that it is a new and a promising avenue that we already are exploring.”
Cultivate all the details in the original article in Nature Neuroscience, August 2020