An international team of researchers, including scientists from UQ’s Queensland Brain Institute (QBI), has identified a new mechanism involved in memory that entails rapid alterations in a particular DNA structure. The study revealed that G-quadraplex DNA (G4-DNA) builds up in neurons and dynamically regulates the activation and suppression of genes responsible for long-term memory formation.The research team made significant progress in understanding the regulation of G4-DNA in the brain, which plays a role in memory formation. They used advanced CRISPR-based gene editing technology to demonstrate the causal mechanism behind this regulation, involving the deposition of the DNA helicase, DHX36. The findings, published in the Journal of Neuroscience, offer the first evidence that G4-DNA is present in neurons and is involved in the expression of different memory states. The study was led by Dr. Paul Marshall at the Australian National University and QBI, along with collaborators from Linköping University, Weizmann Institute of Science, and the University.The University of California Irvine has highlighted the important role that dynamic DNA structures play in memory consolidation. DNA flexibility has been a topic that many scientists considered to be fully understood for decades. The widely recognized structure of DNA is a right-handed double helix, and changes to this structure were thought to only occur during DNA replication and transcription. This structure is made up of two strands of nucleic acid with four bases: adenine (A) and thymine (T), guanine (G) and cytosine (C), which pair together to form the rungs of the DNA ladder. However, it is now known that this is not the complete story. QBI’s Pro
Professor Tim Bredy explains that DNA is capable of taking on various shapes that play an important role in cellular processes.
“The assumption that DNA is a static, right-hand double helix is not accurate,” said Professor Bredy. “More than 20 different DNA structure states have been identified, each potentially playing a different role in controlling gene expression.”
In their recent study, the team has demonstrated that a significant number of these structures are directly involved in regulating gene expression that is dependent on activity, and are necessary for the fo.
Memory formation is influenced by epigenetic modifications, which are well-known for their connection to neuronal plasticity and memory. However, little is is currently known about how local changes in DNA structure impact gene expression.
Cells accumulate G4-DNA when guanine molecules form a stable four-stranded DNA structure. While there is evidence supporting the role of this structure in controlling transcription, its impact on experience-dependent gene expression had not been investigated prior to this study.
The Role of G4-DNA in Memory Regulation
G4-DNA temporarily accumulates in active neurons during the process of learning. The formation of this DNA structure had not been explored in relation to experience-dependent gene expression prior to this study.
The quadraplex structure occurs within milliseconds or minutes, which matches the rate of neuronal transcription in response to an experience.
As a result, the G4-DNA structure can play a role in both enhancing and impairing transcription in active neurons, depending on their activity, in order to facilitate different memory states.
This mechanism demonstrates how DNA dynamically reacts to experience and suggests that it has the ability to store information not only in its code or epigenetically, but also structurally.
Eliminating fear memories
The extinction of conditioned fear memories is a process that involves the suppression of previously learned fear responses. This process is important for adapting to changing environments and preventing the development of anxiety disorders. Research has shown that the quadraplex structure of DNA may play a role in the extinction of fear memories. This suggests that DNA’s structural properties are involved in memory processes beyond its traditional genetic and epigenetic functions. By understanding these mechanisms, researchers hope to develop new strategies for treating anxiety disorders and related conditions.Fear is a vital behavior for survival and its extinction depends on creating new long-term memories that can replace the fear-related ones. The creation of lasting extinction memories relies on coordinated changes in gene expression. Professor Bredy emphasized the importance of activity-induced gene expression in the extinction process, highlighting the temporal interactions between the transcriptional machinery and different DNA structures such as G4-DNA, rather than being solely determined by DNA.The discovery of a highly dynamic transcriptional control device in learning and memory extends our understanding of how DNA functions. This challenges the traditional assumption about sequence or DNA modification.
