While aging works wonders for the taste of our ever-accumulating wine collection, the passage of the years is not as kind to our memories! To fully decipher the processes underlying learning and memory differences in the aging brain, the lab of Iva Zovkic at the University of Toronto Mississauga (Canada) recently expanded on past work into the role of histone variant H2A.Z in the suppression of memories. In their latest report, the team examined the differences in H2A.Z deposition in a brain region critical to memory formation (hippocampus) between young (4 months) and “middle-aged” (15.5 months) mice.
Here’s what they learned about H2A.Z via ChIP-seq:
- H2A.Z enrichment occurs at gene bodies and promoters, with a stronger enrichment at promoters
- CpG islands that flank transcription start sites, and thus exhibit low levels of DNA methylation, display significant H2A.Z enrichment
- Steady-state (basal) H2A.Z levels increase with age at genes involved in transcriptional regulation and the ubiquitin proteasome system
- H2A.Z is a replication independent histone variant, which allows its levels to build up with age in the brain’s post-mitotic neurons
- H2A.Z eviction occurs in response to learning via contextual fear conditioning, regardless of age
- However, despite similar levels of memory formation, aged mice show a reduced H2A.Z eviction response
- While there is a trend for the same genes to be affected, eviction is most prominent and significant at different genes between the ages
- Integration of the H2A.Z peaks with RNA-seq gene expression data revealed a positive association between H2A.Z levels and basal transcription levels, but a negative association with learning induced transcription
- H2A.Z removal induces gene expression
- By employing an adeno-associated virus (AAV) to deliver an shRNA that depletes H2A.Z, the team observed an effect on the learning induced expression of select genes
- There was only a minimal effect on basal gene expression levels
Zovkic shares, “We have thousands of experiences each day, but we only remember things that are in some way important to us. This experiment used a very straightforward learning experience to illustrate that H2A.Z apparently serves to suppress memory, and the removal of this protein appears to…allow long-lasting memories to form.”
“We’re always trying to find molecular bases for memory, and discovering how genes related to memory are turned on and off is a step in a positive direction. Identifying H2A.Z as a unique protein that is involved with memory and increases with aging could be a big deal for creating genetic or pharmaceutical therapies for age-related cognitive decline and dementia. H2A.Z is a relatively specific therapeutic target.”
Evict the rest of your brain’s H2A.Z over at Cell Reports, January 2018