Most epigenetic studies are music to our ears, but do you prefer “The Rolling Histones,” “Run-5mC,” or something more classical while working in the lab? Well, move over rock and hip-hop, as an epigenetic masterpiece now describes how a long non-coding RNAs (lncRNA) epigenetically conducts a synaptic symphony to “orchestrate” fear extinction memory.
Previous pleasant-sounding research from Wei-Siang Liau and Timothy W. Bredy (University of Queensland) had stressed the role of nuclear lncRNAs in the activity-dependent epigenetic regulation of gene expression associated with fear-related learning. As lncRNAs also accumulate at synapses in response to neural activity, the in-tune team explored a potential link between synaptic lncRNAs and the localized regulation of fear extinction by employing very specific “instruments” – lncRNA capture-sequencing (to map synapse-enriched lncRNA expression in the infralimbic prefrontal cortex of adult male mice), single-molecule tracking in live cortical neurons, and a highly-specific and state-dependent RNA knockdown approach.
Let’s hear more on this symphonic, synaptic, lncRNA-led epigenetic ensemble conducted by Liau, Zhao, and colleagues:
- LncRNA capture-seq (specifically designed for the identification of low-abundance lncRNAs) identifies lncRNAs accumulating at synapses, which include a mature localized isoform of the Gas5stress-associated lncRNA
- Other identified synapse-enriched alternatively spliced lncRNAs are unannotated or pseudogenes, which recent studies have indicated may be lncRNAs
- RNA immunoprecipitation and mass spectrometry and single-molecule imaging reveal how Gas5 regulates the activity-dependent trafficking and clustering of RNA granules in dendrites with the help of the G3BP2 and CAPRIN1 RNA binding proteins
- G3BP2 and CAPRIN1 form a stable complex in response to stress, which serves to regulate condensate localization and dynamics
- Cell-type-specific, activity-dependent, and synapse-specific Gas5 knockdown increases intrinsic neuronal excitability, prompts localized Gas5-containing RNA granule disassembly, and impairs long-term extinction memory formation
- Gas5 may function as a synapse-specific scaffold to coordinate the clustering of “memory” granules in an activity-dependent manner to organize the learning-induced activity of critical proteins involved in local protein translation and hence control the synaptic mechanisms underlying fear extinction memory
While this well-conducted synaptic symphony provides evidence for the role of lncRNAs in orchestrating fear extinction memory, more sublime future classics remain to be debuted. Ongoing work by this team of epigenetic instrumentalists hopes to deepen the coverage of lncRNAs, move beyond input requirements and achieve cell-type resolution, and explore the functional and mechanistic roles of individual synaptic lncRNAs and their interacting partners in different activity-dependent conditions and additional learning situations.
Senior author Timothy Bredy notes that “There’s a lot more happening with these kinds of RNA molecules than we first thought and that fact 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.”
For more on how a lncRNA helps to conduct a synaptic symphony to orchestrate fear extinction memory, see Nature Communications, November 2023.