Memory is one fancy cellular function that seems to be the niche of the epigenome. Through it a cell can remember its identity and past exposures. But what about that other type of memory? Ya know, neuroepigenetic memory.

We’ve already seen that histone methylation has a role in long-term memories and altered histone acetylation (H4K12) is involved in age related memory decline. Adding to the growing evidence of epigenetic memory is new research from the lab of J. David Sweatt, where the talented team have shown that histone subunit exchange (H2A.Z) is behind the consolidation of memory in the brain.

Memory Mechanisms:

Memory is a complex multi-stage process that starts in the brain’s hippocampus. In the hippocampus a process known as cellular consolidation occurs. After that memories can be ‘downloaded’ to another part of the brain known as the prefrontal cortex. This process is called systems consolidation. Both consolidation processes are dependent on none other than epigenetic mechanisms. The one added to the roster today, is histone variant exchange, in which the standard (canonical) histones are replaced with special variants. The field of histone variant exchange hasn’t yet gotten the attention it deserves, particularly when it comes to one of the most complex biological processes: cognition.

Neuroepigenetic Histone Subunit Exchange:

ChIP and RNA-Seq experiments on the hippocampus and prefrontal cortex of fear conditioned mice revealed:

Some interesting tissue dynamics in the hippocampus (CA1 region): At the transcription start sites (TSS) of memory promoting genes H2A.Z was reduced, while at the TSS of memory suppressing genes it was increased.

By interfering with H2A.Z binding via some brain surgery to deliver H2A.Z shRNA they saw that: H2A.Z depletion in the CA1 region resulted in better memory of the fearful event and increased Bdnf and Arc expression. H2A.Z subunit exchange is not involved in the expression of baseline memory genes but is rather a dynamic response to learning. H2A.Z depletion in the prefrontal cortex affected long-term but not short-term memory.

Thus H2A.Z subunit exchange regulates gene expression and restrains the formation of recent and remote memories in the brain, serving as a negative regulator of the processes of consolidating memory in both the hippocampus and the prefrontal cortex.

When it comes down to it, this paper offers some very convincing evidence that histone H2A.Z subunit exchange functions as a novel mechanism in the molecular basis of cognitive function, while also providing a new target for drug development. Lead author Iva Zovkic concludes that “Our data identify histone variant exchange as a novel branch of epigenetics that regulates cognitive function. Although we focused specifically on H2A.Z, all histones except for H4 have multiple variants and our data suggest that their incorporation into nucleosomes can have tremendous implications for shaping behavioral outcomes.”

Go and learn how to remember in Nature, December 2014.