G-quadruplex DNA or G4 DNA: a dynamic structure
Left: molecular structure of G-quadruplex DNA. On the right, visualization and coloring of this DNA in the nuclei of human cells and in chromosomes (Source: Jean-Paul Rodriguez and Giulia Biffi, University of Cambridge)
An international research team including scientists from the Queensland Brain Institute, an Australian neuroscience research institute, has discovered an important mechanism involved in the formation of memory and our memories.
The results of this study focus on the dynamic behavior of a particular DNA structure known as G-quadruplex DNA or G4 DNA. The team has just highlighted the essential role of this structure in regulating the expression of genes associated with long-term memory.
This study, published in Journal of Neuroscience, constitutes the first evidence that this G-quadruplex DNA is found in neurons and that it is actively involved in the modulation and expression of different memory states.
What is G-quadruplex DNA or G4 DNA? Usually, the DNA of our cells adopts a standard conformation called B-DNA. This is the famous DNA double helix which was described for the very first time by James Watson (born in 1926), Francis Crick (1916- 2004) and Maurice Wilkins (1916-2004) in 1953.
Although strongly present in all our cells, this conformation of DNA is not the only One. DNA can in fact fold into other structures such as A-DNA and Z-DNA which are also double helices, but a little different.
Besides these double helix structures, DNA can adopt other conformations such as that of the hairpin, the Holliday junction, triplex DNA which is a three-stranded DNA and finally G-quadruplex DNA.
Great importance in memory consolidation
Quadruplex-like structures form in nucleic acids such as DNA and RNA. In such a structure, four guanines are held together by a somewhat special type of bond called Hoogsteen pairing.
Structures are thus formed not with two strands as in B DNA, but structures with four strands. A monovalent cation (metal ion carrying a positive charge) intervenes in this structure to stabilize it.
G-quadruplex DNA is one of about twenty different states of DNA that researchers have identified to date. Each of these states potentially plays a particular role in gene regulation.
During this new study, which focuses primarily on the G4 structure, the researchers discovered that it accumulates in nerve cells in response to learning.
During a learning phase, this G-quadruplex DNA accumulates temporarily in neurons. The formation of G4 DNA is very rapid, taking only a few milliseconds.
For this study, the researchers worked with mice. In this animal, they realized that G4 DNA is involved in both increasing and decreasing transcription in active neurons, depending on their activity, to enable different memory states.
This mechanism is very interesting, because it highlights the way in which DNA reacts to an experience, showing that it is not static, but dynamic. The results of this study suggest that DNA has the capacity to store information in its code, but also in its structure.
Fear extinction, an essential mechanism for survival
One of the practical implications of this research is its potential impact on understanding and potentially treating memory-related conditions, such as fear extinction, a critical survival mechanism.
Fear is an emotion felt by everyone. It arises from the threat of physical, emotional or psychological harm, real or imagined. Although considered a negative emotion, fear actually plays an essential role in our safety, because it mobilizes us in the face of danger.
Extinction of this fear relies on the formation of new long-term memories with similar environmental elements. These new memories compete with the memory linked to fear and replace it.
The formation of these new memories depends on coordinated changes in gene expression. This is a process that depends on temporal interactions between the transcriptional machinery and a variety of DNA structures such as G-quadruplex DNA.
This discovery not only expands the fundamental understanding of how DNA functions as a transcriptional control device, but it also paves the way for future studies that could lead to innovative therapies for various psychiatric disorders, taking advantage of the dynamic nature of DNA in the brain.
Source :
Paul R. Marshall, Joshua Davies, Qiongyi Zhao, Wei-Siang Liau, Yujin Lee, Dean Basic, Ambika Periyakaruppiah, Esmi L. Zajaczkowski, Laura J. Leighton, Sachithrani U. Madugalle, Mason Musgrove, Marcin Kielar, Arie Maeve Brueckner, Hao Gong, Haobin Ren, Alexander Walsh, Lech Kaczmarczyk, Walker S. Jackson, Alon Chen, Robert C. Spitale and Timothy W. Bredy, “DNA G-Quadruplex Is a Transcriptional Control Device That Regulates Memory,” Journal of Neuroscience, 10 April 2024, 44 (15) e0093232024; DOI: https://doi.org/10.1523/JNEUROSCI.0093-23.2024
