The Eiffel Tower may live long in the memory, and La Sagrada Familia will be remembered for eons (when they finish it!), but can any structure truly rival DNA? Now, a new study describes how one of DNA’s many unforgettablestructural forms – G-quadruplex DNA (G4-DNA) – helps to regulate the gene expression profiles controlling fear extinction memory.
Researchers guided by Paul Marshall (now a group leader at the Australian National University) in the laboratory of Timothy W. Bredy (Queensland Brain Institute) previously discovered an association between neural activity and conformationally left-handed DNA (Z-DNA), which modulates transcription and the strength of fear-related memories. The team wasn’t afraid to inquire whether additional DNA structures played similar roles, and their subsequent research focused on how G4-DNA formation and its DHX36 helicase-mediated resolution impacted experience-dependent gene expression and memory.
Let’s hear from Marshall and colleagues on how an unforgettable DNA structure regulates gene expression and memory:
- DHX36 becomes active in the presence of G4-DNA in medial prefrontal cortex neurons during late-phase fear consolidation and extinction learning
- G4-DNA-seq and DHX36 IP-seq in fear-conditioned mice undergoing extinction training reveals that DHX36 downregulation prompts G4-DNA accumulation within intronic sequences and at TSSs
- DHX36 regulates G4-DNA in neurons at genes critically important for neuronal plasticity (e.g., gephyrin (Gphn) and neural cell adhesion molecule L1-like (Chl1)) in an experience-dependent manner
- G4-DNA associates with reduced and increased RNA expression over short time scales during fear extinction learning
- DHX36 downregulation leads to the downregulation and upregulation of 64 and 101 genes, respectively
- Downregulated genes include those associated with neuronal processes (ion channels and actin-binding), while increased genes associated with alternative splicing and ion channel binding
- DHX36 downregulation reveals that G4-DNA primarily acts as a gene silencer in neurons and that accumulation promotes Pol II stalling within learning-related genes
- Consolidation of fear extinction memory requires DHX36, as preventing G4-DNA removal impairs memory processes
- A synapsin 1–driven dCas9-DHX36 construct directly defines a role for DHX36 in the regulation of G4-DNA in neurons (Gphn and Chl1 as targets) by linking site-specific resolution to impaired fear extinction memory
- The findings confirm that this structural form of DNA regulates learning-induced gene expression in a state-dependent and gene-specific manner, which can have opposing effects depending on the phase of memory formation
This well-structured, truly memorable study provides evidence for the direct participation of G4-DNA in fear-related memory and implies a role for dynamic DNA structures in memory consolidation. Indeed, the authors show that neuronal transcription and the expression of different memory states involve this structural form of DNA. Future structural projects headed by this fearless team may investigate G4-DNA formation, stability, and resolution in additional cell types and activity states.
For more on the regulation of gene expression and memory via an unforgettable DNA structure, see the Journal of Neuroscience, April 2024.