RESEARCH HIGHLIGHT

Cell Research (2014) :1-2.
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Another twist in the histone memory code
Cell Research advance online publication 24 October 2014; doi:10.1038/cr.2014.134

Transcription is a highly regulated
process and several studies have examined the role of transcription factors and various epigenetic regulators
in memory formation. In a recent paper in Nature, Zokvic and colleagues
show an important role for a novel
regulator of chromatin structure (theincorporation of histone variants) inmemory formation.
It has been known since the 1960s
that the formation of long-term memory
critically depends on transcription. For
example, Agranoff and colleagues
showed that the RNA synthesis inhibitor actinomycin D impaired memory
formation in goldfish if administered
immediately after training, but had noeffect on memory if administered 1 hafter training [1]. Transcription is highly
regulated and involves a coordinated response of several players and processes,
including transcription factors (regulatory proteins which activate or inhibit
the transcription of DNA by binding tospecific DNA sequences) and chromatin
remodeling (which allows the accessof transcription factors to the DNA).
Important roles for transcription factors(including CREB, MEF2 and others) [24] and various chromatin modifications[5, 6] in memory formation have beenpreviously described.
Roughly 2 meters of DNA is packed
into the nucleus of all eukaryotic cells.
Cells are able to house this vast quantity of DNA because the negativelycharged DNA is tightly wound aroundpositively-charged histone proteins.
Histone-wrapped DNA (chromatin) is
relatively inaccessible to the transcription machinery. However, parts of theDNA can “unwind” thereby allowing

access to transcription factors. The
conformational state of the DNA is also
mediated by several processes. For instance, histones may be post-transcriptionally modified (e.g., phosphorylation,methylation, acetylation, sumoylation
and ubiquitination [7]). The combinations of these histone “marks” (sometimes referred to as the “histone code”)
determine which transcription factors
can bind to specific DNA regions toregulate the expression of particulargenes. Chromatin architecture may also
be modulated by the incorporation ofhistone variants [8]. The core histones
come in 4 flavors (H2A, H2B, H3 andH4). Histone variants are non-allelicforms of the conventional core histones
which are expressed at comparatively
lower levels. All conventional histones,except H4, have histone variants. One of
the most highly conserved histone variant is H2A.Z (which may replace H2A).
Although great strides have been
made in understanding the transcriptional processes mediating memory
formation, the present paper by Zovkic
and colleagues [9] represents the first toexamine a potential role for the incorporation of histone variants in memory
formation. This is remarkable because
little is known about the function of histone variants in general, and even less isknown about the role of histone variant
replacement in memory. To examine
long-term memory formation in mice,
Zovkic and colleagues used Pavlovian
fear/threat conditioning in which micelearn to associate a particular place(context) with an aversive footshock.
When subsequently placed back in thecontext (1 day or even 30 days later),mice show a defensive response (freez-ing behavior). This type of context
memory initially depends on the dorsal
hippocampus, but over time, this memory trace is thought to re-organize in thebrain, such that it becomes increasingly
dependent on the cortex, including inparticular the medial prefrontal cortex(mPFC) [10]. This process (referred toas systems consolidation) is thought tobe mediated by time-limited interactions
between the hippocampus and cortex.
Contextual memories are thought to be
rapidly encoded in the hippocampus
whereas this knowledge if more slowly
is encoded in cortical circuits.
The current paper examined the roleof the histone variant H2A.Z during
memory consolidation over this same
extended time course. First, Zokvic
and colleagues found that H2A.Z levels are decreased in the CA1 regionof the dorsal hippocampus in the minutes, but not hours, following training(consistent with the notion that H2A.Z
plays a time-limited role in initialmemory consolidation). This posttraining decrease in H2A.Z level wasaccompanied by a decrease in H2A.Z
binding to key transcriptional start sitesof several “memory promoter” genes(e.g., Npas4, Arc, Fos, Egr1), but anincrease in incorporation of H2A.Z intoa “memory repressor” gene (Ppp3ca).
Together, these data suggest that H2A.Z
in the dorsal hippocampus may serve tonegatively regulate memory formationin the minutes following training. To
test this idea, this group examined theeffects of locally decreasing H2A.Zlevels using viral vectors to express aconstruct that reduces levels of H2A.ZmRNA and protein. Microinjecting thisinhibitory construct into the dorsal hip-npg

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pocampus of mice prior to fear training
increased fear memory (freezing) measured 1 day after training, suggestingthat H2A.Z normally restricts memory
formation. The memory enhancement
was also observed 30 days following
training, suggesting that relieving theinhibitory brake of H2A.Z in the dorsal
hippocampus enhances initial memory
consolidation and that this strengthened
hippocampal trace also instructs thecortex. However, what about the roleof H2A.Z in the cortex?
To examine this, Zovkic and colleagues microinjected their H2A.Zantagonist into mPFC prior to fear
conditioning. Memory tested either 7or 30 days after training was enhanced.
However, memory was unaffected if
tested 1 day after training. This finding
suggests that in the mPFC H2A.Z is
not important for the expression of theinitial memory trace, but that H2A.Z
normally restrains the mPFC component of the memory trace that gradually emerges following training. These
results agree with the general notionthat cortical memory circuits integrate
information more slowly than the hippocampus. Furthermore, they suggestthat similar processes are engaged atdifferent times in these different brain
regions, reflecting, perhaps, evolution’s
penchant for re-purposing mechanisms.
Memory formation and storage
involves an orchestrated response of
finely-tuned processes across several
brain regions. By showing a unique,brain region-dependent and timelimited role for histone variants in theprocess, the current study adds yet another layer of complexity (a new twistin the histone code) to this process. We
stand in awe of this complexity and arereminded of that sentiment forwarded
by a pioneering memory researcher.
To paraphrase Karl S Lashely [11], we
sometimes feel, in reviewing the evidence, that the necessary conclusion isthat learning (and retention) is just notpossible. It is difficult to conceive of aset of mechanisms that can be so finely
tuned to allow for it. Nevertheless, inspite of such evidence against it, learning sometimes does occur. Although
the findings of Zovkic and colleagues
are novel and important, they also serve
to emphasize how little we understandabout this fundamental process.

Sheena Josselyn1, 2, 3, 4,Paul W Frankland1, 2, 3, 4

Program in Neurosciences and Mental Health,The Hospital for Sick Children, Toronto, Ontario
M5G 1X8, Canada; 2Institute of Medical Science,
University of Toronto, Toronto, Ontario M5S 1A8,Canada; 3Department of Psychology, Universityof Toronto, Toronto, Ontario M5S 3GM, Canada;
4
Department of Physiology, University of Toronto,Toronto, Ontario M5S 1A8, Canada
Correspondence: Paul W Frankland
E-mail: paul.frankland@sickkids.ca
1

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1

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