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Epigenetic Regulation Has Role in Memory Formation, Anxiety, Researchers at ASHG Say

SAN DIEGO (GenomeWeb) – Epigenetic regulation of genes is involved in processes and conditions as disparate as memory formation and anxious temperament, according to researchers presenting at the American Society of Human Genetics annual meeting. These epigenetic marks also present a possible way to treat related disorders.

Duke University's Aaron Towers and his colleagues hypothesized that epigenetic regulation, in particular through TET1, plays an important role in the formation of memories. TET1 is involved in DNA demethylation and converts 5-methylcytosine into 5-hydroxymethylcytosine. It, he noted, is present at high levels in the hippocampus, a brain region involved in memory formation, alongside 5-hydroxymethylcytosine.

He and his colleagues developed TET1 knockout mice and studied memory formation in the mice. In one memory test, in which knockout and wildtype mice were exposed to known and novel stimuli, the knockout mice explored the known stimuli as much as the did the novel one, while the wildtype mice spent more time examining the new stimuli.

Additionally, through the other memory test, which involved the social transmission of food preferences, the knockout mice appeared to forget what they learned from their peers about food while the wildtype mice did not.

This, Towers said, indicates that the knockout mice have a deficit in their short-term memory.

To examine activity-induced gene expression changes in the mice, three pairs of knockout and wildtype mice were given electroconvulsive shocks and their RNA-seq profiles determined. From this, Towers and his colleagues identified 188 downregulated genes and 39 upregulated genes in the knockout mice.

Through a gene ontology analysis, they found an enrichment of extracellular matrix genes, which are involved in synaptic plasticity, among these differentially expressed genes. In particular, Towers said, they found that Npas4, a master memory gene regulator, was significantly downregulated in the knockout mice.

"Our study suggests a role for TET1 in regulating gene expression [that is] important for memory formation," the session abstract said. "A better understanding of the molecular mechanisms of memory formation will be critical for finding future therapies for human memory disorders."

Meanwhile, Reid Alisch at the University of Wisconsin-Madison reported a role for epigenetic regulation in anxiety. He and his colleagues performed reduced representation bisulfite sequencing on 23 male rhesus monkeys that are a nonhuman primate model of anxious temperament.

Through that approach, they identified more than 5,000 CpG sites associated with anxious temperament. These sites, Alisch said, were significantly overrepresented on chromosome 1 and chromosome 19. The CpG regions also implicated genes like the glutamate receptors GRIN1 and GRM5, which have been linked to psychiatric-related disorders previously.

In the same 23 rhesus monkeys, the researchers examined gene expression levels in the central nucleus of the amygdala, a part of the brain involved in anxious temperament.

The methylation patterns they found were associated with the expression of 22 genes, including GRIN1 and GRM5, which are involved in cell development and maturation. Also among those 22 genes were BCL11A and JAG1, both of which have roles in neurodevelopment, including axon branching for the former and synaptic plasticity for the latter.

"[These are] very interesting targets for us to investigate in patients with high anxiety," Alisch said, noting that molecular technologies could be used to modify their functions.