RNA, like DNA, is present in all living cells. Historically, it was thought to primarily serve to transform the information encoded in DNA into the body’s proteins. However, large scale genome sequencing projects at the turn of the century changed our perspective of RNA.
Where we once believed that only a small percentage of RNAs contained useful information, we now know that the thousands of RNAs that do not carry genetic information for protein encoding, are still, in fact, extremely useful.
Despite this leap, we still don’t have a complete grasp of the total number of RNAs encoded in the genome. Novel classes of RNA continue to be discovered.
Cutting-edge technologies, such as long-read sequencing, are giving researchers, like Professor Timothy Bredy unprecedented insights into cells to better understand the functional roles of various classes of RNA.
The Bredy lab’s research into the RNA-based mechanisms regulating neuronal capacity during fear-related learning and memory have clearly illustrated that our genes alone don’t dictate destiny.
Why is epigenetics important to the pursuit of understanding the brain?
We now understand that learning and memory are not linear processes governed only by protein synthesis. Gene-environment interactions affect cellular function and real-time brain adaptation. We can only attempt to understand learning and memory if we can unravel how these underlying dynamic mechanisms are affecting cell function.
How has the RNA revolution challenged our understanding of brain function?
The central dogma of molecular biology has been that there is a unilateral flow of information from DNA to mRNA to protein. We now know that there are in fact many different classes of RNA, many of which are expressed in the brain. Their function extends far beyond their role as a signalling intermediate.
Recent evidence indicates that different non-coding RNAs are directly involved in learning and memory. For example, my lab discovered that microRNAs are critically involved in the capacity to form long-lasting memories for fear extinction.
Why is RNA so crucial to an understanding of epigenetics?
The neuroepigenetic view of learning and memory suggests that DNA, protein, and RNA interact and influence each other to control the cell holistically.
Diverse forms of RNA have already emerged as key regulators of gene expression, and their importance in cell regulation continues to be explored.
For example, a recent discovery has been the epigenetic regulation of RNA through chemical modification. To date, there are at least 170 ‘epitranscriptomic’ modifications that are known to occur in RNA.
Your research has identified such chemically-tagged RNA’s involved in learning and memory. What exactly is it that you found?
We identified a population of learning-related RNAs that accumulate near the synapse. These RNA harbour a specific chemical tag called N6-methyladenosine (m6A), which effectively modifies the RNA, so that they can communicate with specific proteins and alter the synapse.
Traditionally, the science of RNA in the brain has focused on what’s happening within the nucleus, but we found a significant number of these m6A-modified RNAs near the synapse. This localisation indicates its role in regulating synaptic plasticity, which we know is a fundamental aspect of learning and memory.
Dr Umanda Madugalle and Dr Wei-Siang Liau, you were the lead authors on this paper. You discovered these m6A-modified RNAs near the synapse. How has this finding contributed to your understanding of how fear-related memories are formed?
We found these m6A-modified RNAs near the synapse and we discovered several new synapse-specific m6A binding proteins (or “readers”) that interact with these modified RNAs.
This discovery allowed us to determine the functional role of m6A-modified RNA molecules in the formation of new memories.
By examining one such RNA, Malat1, we discovered the key proteins that interact with this RNA and support the processes related to forming long-lasting memories in the context of fear extinction.
What are the implications of this discovery?
The impairment of fear extinction memory is associated with post-traumatic stress disorder (PTSD).
When Malat1 is chemically decorated with m6A, this allows it to interact with different proteins in the synaptic compartment, which can then alter the mechanisms involved in the formation of fear extinction memory.
By understanding where, when, and how an RNA molecule is activated and by having a precise marker, we can identify the target for potential PTSD therapies.
Your most recent research demonstrated RNA’s role in fine-tuning the cellular functions of the brain. In what way?
We demonstrated that a non-coding RNA known as Gas5 coordinates the trafficking and clustering of RNA molecules inside the long processes of neurons, and orchestrates neuronal excitability in real time that contributes to learning and memory.
Dr Wei-Siang Liau and Dr. Qiongyi Zhao, you were the lead authors on this paper. How has this finding influenced your understanding of RNA molecules?
This finding highlights that there’s a lot more happening with these kinds of RNA molecules than we first thought; and that they influence cellular function on a millisecond timeframe, which mirrors the real-time changes in synaptic function that happen in the brain during learning, is extraordinary.
Non-coding RNA may be the missing link to understanding how the brain processes critically important inputs that lead to the formation of memory.
RNA-based treatments offer significant promise for new precision therapies and the field is rapidly progressing toward the development of new diagnostic and therapeutic tools for brain disorders.
The Centre for RNA in Neuroscience at QBI was established to spearhead the development and application of this new and exciting technology.
An Australian Neuroscience Symposium (ANS) Satellite “RNA in Brain Function and Disease” will be held at QBI on December 8, 2023. With internationally acclaimed Plenary Speaker, Prof Gene Yeo (University of California, San Diego), a world leader in RNA biology and RNA therapeutics (www.yeolab.com), this meeting will bring together national leaders in neuroscience and RNA biology to discuss the latest findings in this important and rapidly emerging area of research. Register here.