QBI Neuroscience Seminar: Tet-mediated DNA hydroxymethylation within the prefrontal cortex as a mechanism for the formation and maintenance of fear-related memory
Event Details
- Date:
- Wednesday, 09 December 2015 - Wednesday, 09 December 2015
- Time:
- 12:00 pm - 1:00 pm
- Room:
- QBI Level 7 Auditorium
- UQ Location:
- Queensland Brain Institute (St Lucia)
- URL:
- http://www.qbi.uq.edu.au/neuroscience-seminars
- Event category(s):
Event Contact
- Name:
- Ms Deirdre Wilson
- Phone:
- 3346 6300
- Email:
- d.wilson5@uq.edu.au
- Org. Unit:
- Queensland Brain Institute
Event Description
- Full Description:
- Xiang Li of the Queensland Brain Institute, University of Queensland presents: Tet-mediated DNA hydroxymethylation within the prefrontal cortex as a mechanism for the formation and maintenance of fear-related memory.
Abstract:
Epigenetic mechanisms are critically involved in the regulation of gene expression underlying learning and memory. Dynamic variation in cytosine methylation has emerged as a primary mechanism underlying experience-dependent plasticity in the nervous system and in the formation of fear-related memory. However, cytosine methylation is not the only DNA modification in eukaryotic genome. Recent studies have shown that 5-methylcytosine (5mC) can be oxidized and converted to 5-hydroxymethylaton (5hmC) by the ten-eleven translocation (Tet) family proteins. Moreover, 5hmC has been found to be highly enriched in the adult brain, can be dynamically regulated by neural activity, and accumulates across the lifespan. During my PhD training, we build upon the hypothesis that Tet-mediated accumulation of 5hmC may underpin the novel cellular and molecular processes that contribute to fear extinction memory. In support of this hypothesis, we first demonstrate that Tet3 gene expression is associated with neuronal activation in vitro. We next found that the expression of Tet3 mRNA, not Tet1 mRNA, is specifically induced after fear extinction training, in vivo.
To expand on these findings, we performed high-throughput genome-wide sequencing for 5hmC. This was enabled by sequencing samples derived from the infralimibic prefrontal cortex (ILPFC) of mice. We developed a novel protocol that allows one to profile the genome-wide landscape of 5hmC within the ILPFC of individual mice using low input DNA. By adopting this protocol, we mapped out the accumulation of 5hmC across the genome in the ILPFC following fear acquisition and fear extinction. We have found that, upon behavioural training, there is a dramatic redistribution of 5hmC in response to learning. Moreover, by comparing the genome-wide data between fear conditioned and fear extinction-trained mice, we identified 233 unique genomic loci that exhibit accumulation of 5hmC after extinction training. A gene ontology analysis revealed that 38 of 233 genomic loci are associated with genes encoding proteins that are known to be important for synaptic activity.
To further explore the relationship between Tet3, 5hmC and fear extinction learning, we investigated the functional relevance of a 5hmC peak within an intronic region of gephyrin, a gene that has previously been shown to play a critical role in fear extinction. We found fear extinction leads to increase occupancy of Tet3 at the gephyrin locus and leads to the accumulation of 5hmC, which promotes gephyrin gene expression. Tet3-mediated 5hmC accumulation at this locus also promotes a poised euchromatin state that may lead to the priming of transcription. By using lentiviral-mediated knockdown of Tet3, the above-mentioned effects were completely abolished. Thus, this is the first evidence showing that, in the adult brain, fear extinction promotes Tet3-mediated accumulation of 5hmC, and correlates with learning-related chromatin modifications that underpin the formation of fear extinction memory.
Directions to UQ
- Google Map:
-
- Directions:
- St Lucia Campus | Gatton campus.
Event Tools
Share This Event
Print
Email
Share
