RNA sequencing reveals ‘Junk DNA’ key to controlling fear

A piece of “junk DNA” could be the key to extinguishing fear-related memories for people struggling with post-traumatic stress disorder (PTSD) and phobia, according to a study from The University of Queensland.

An international research project, led by the Queensland Brain Institute’s Associate Professor Timothy Bredy, discovered the new gene while investigating how the genome responds to traumatic experiences.

“Until recently, scientists thought the majority of our genes were made up of junk DNA, which essentially didn’t do anything.” Dr Bredy said.

“But when researchers began to explore these regions, they realised that most of the genome is active and transcribed.”

Using a powerful new sequencing approach, Dr Bredy’s team identified 433 long non-coding RNAs from relatively unknown regions of the human genome.

“The technology is a really interesting way to zero in on sites within the genome that would otherwise be masked,” Dr Bredy said.

“It’s like harnessing the power of the Hubble Telescope to peer into the unknown of the brain.”

A new gene, labelled ADRAM by the researchers, was found to not only act as a scaffold for molecules inside the cell, but also helped coordinate the formation of fear-extinction memory.

LncRNAs derived from enhancer elements are induced by fear extinction learning and correlate with proximal protein-coding gene expression in the adult prefrontal cortex

(A) Schematic of the behavioral protocol used to collect ILPFC tissue after fear extinction training. (B) Genomic distribution of ATAC peaks in Arc+ neurons that have been activated by fear extinction learning. (C) The Venn diagram highlights 434 proximal lncRNAs overlapping with lncRNA capture-seq, Arc+ EXT ATAC-seq, as well as H3K27ac-, CBP-, and H3K4me1-enriched genomic regions. (D) Heatmap of eRNA-associated mRNA expression in quiescent (ARC− EXT) versus activated (ARC+ EXT) neurons (n = 3 biological replicates for ARC− EXT; n = 4 biological replicates ARC+ EXT; red, decreased expression; blue, increase expression). (E) Gene ontology (GO) analysis for proximal protein-coding genes located <10 kb downstream of the 434 eRNA loci. The top 30 significantly enriched GO terms are shown in the dot plot.

Until now, there have been no studies devoted to understanding these genes, or how they might influence brain function in the context of learning and memory.

“Our findings suggest that long non-coding RNAs provide a bridge, linking dynamic environmental signals with the mechanisms that control the way our brains respond to fear,” Dr Bredy said.

“With this new understanding of gene activity, we can now work towards developing tools to selectively target long non-coding RNAs in the brain that directly modify memory, and hopefully, develop a new therapy for PTSD and phobia.”

SourceThe University of Queensland

Wei W, Zhao Q, Wang Z, Liau WS, Basic D, Ren H, Marshall PR, Zajaczkowski EL, Leighton LJ, Madugalle SU, Musgrove M, Periyakaruppiah A, Shi J, Zhang J, Mattick JS, Mercer TR, Spitale RC, Li X, Bredy TW. (2022) ADRAM is an experience-dependent long noncoding RNA that drives fear extinction through a direct interaction with the chaperone protein 14-3-3. Cell Rep 38(12):110546. [article]

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