Discovery of a new mechanism for DNA memory

summary: Researchers have identified a new mechanism that affects memory formation through changes in the structure of DNA, specifically G-quadruplex DNA (G4-DNA). Their study reveals that G4-DNA accumulates in neurons, dynamically affecting gene activation and repression, which is essential for long-term memory.

By using CRISPR technology, the team demonstrated that the DNA helicase DHX36 directly regulates G4-DNA structures in the brain. This discovery not only changes our understanding of the role of DNA in memory, but also opens new avenues of investigation into memory-related disorders.

Key facts:

  1. The study provides the first evidence for the presence of G4-DNA in neurons, highlighting its functional role in regulating gene expression associated with memory.
  2. Researchers used advanced CRISPR-based gene editing to determine how G4-DNA structures are organized in the brain, and found a critical role for the DNA helicase DHX36.
  3. The findings suggest that the structure of DNA, beyond just its sequence, plays a crucial role in how experiences are encoded in the brain, which may impact treatments for memory-related conditions.

source: Queensland Brain Institute

An international collaborative research team, including scientists from the Queensland Brain Institute (QBI) at the University of Queensland, has discovered a new mechanism underlying memory that involves rapid changes in a specific DNA structure.

The team found that G-quadraplex DNA (G4-DNA) accumulates in neurons and dynamically controls the activation and repression of genes underlying long-term memory formation.

In addition, using advanced CRISPR-based gene editing technology, the team revealed the causal mechanism underlying G4-DNA regulation in the brain, which involves site-directed deposition of the DNA helicase, DHX36.

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The new study published in Journal of NeuroscienceProvides the first evidence that G4-DNA is present in neurons and is functionally involved in the expression of various memory states.

The study, conducted by Dr Paul Marshall from the Australian National University, QBI and a team of collaborators from Linköping University, the Weizmann Institute of Science and the University of California Irvine, highlights the role that dynamic DNA structures play in memory consolidation.

DNA flexibility

For decades, many scientists have considered the DNA issue to be resolved. DNA is widely recognized as a right-handed double helix, with changes to this structure occurring only during DNA replication and transcription.

This structure contains two strands of DNA containing four bases: adenine (A), thymine (T), guanine (G) and cytosine (C), which pair together to form the rungs of the DNA ladder.

We now know that this is not the whole story. QBI's Professor Tim Brady explains that DNA can take on a variety of conformational states that are functionally important for cellular processes.

“DNA topology is much more dynamic than a fixed right-handed double helix, as most researchers in the field assume,” Professor Priddy said.

“There are actually more than 20 different states of DNA structure that have been identified so far, each of which likely plays a different role in regulating gene expression.”

In the new study, the team has now shown that a large proportion of these structures are causally involved in the regulation of activity-dependent gene expression and are required for memory formation.

Although epigenetic modifications have a well-established association with neuronal plasticity and memory, to date little is known about how local changes in DNA structure affect gene expression.

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G4-DNA accumulates in cells when guanine folds into a stable four-stranded DNA structure. While there is evidence for the role this structure plays in transcriptional regulation, prior to this study, its involvement in experience-dependent gene expression had not been explored.

G4-DNA regulates memory

G4-DNA transiently accumulates in active neurons during learning. This quaternary structure is formed within milliseconds or minutes, at the same rate of neural transcription in response to experience.

Thus, the G4-DNA structure could be involved in promoting and weakening transcription in active neurons, depending on their activity, to enable different memory states.

This mechanism sheds light on how DNA responds dynamically to experience, and suggests that it has the ability to store information not only in its code or genetically, but structurally as well.

– Extinguishing memories of fear

Extinction of conditioned fear is an important behavioral adaptation for survival. Fear extinction depends on the formation of new, long-term memories with similar environmental elements, to compete with and take over the memory associated with fear.

The formation of long-term extinction memories depends on coordinated changes in gene expression.

Professor Priddy said it was now clear that the activity-induced gene expression underlying extinction is a tightly coordinated process.

“This process relies on temporal interactions between the transcription machinery and a variety of DNA structures, including G4-DNA, rather than being determined solely by DNA sequences or DNA modification as is often assumed.

“This discovery expands our understanding of how DNA functions as a highly dynamic transcriptional control device in learning and memory.”

About genetics, learning and memory research news

author: Tim Brady
source: Queensland Brain Institute
communication: Tim Brady – Queensland Brain Institute
picture: Image credited to Neuroscience News

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Original search: Closed access.
DNA G-Quadruplex is a transcriptional control device that regulates memory“By Tim Brady et al. Journal of Neuroscience

a summary

DNA G-Quadruplex is a transcriptional control device that regulates memory

The conformational state of DNA adjusts the rate of transcription and RNA abundance.

Here, we report that G-quadruplex DNA (G4-DNA) accumulates in neurons, in an experience-dependent manner, and that this is required for the silencing and transient activation of genes critically involved in learning and memory in male C57/BL6 mice.

In addition, site-specific resolution of G4-DNA by dCas9-mediated deposition of the DHX36 helicase impairs fear extinction memory. Dynamic DNA structural states thus represent a key molecular mechanism underlying memory consolidation.

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