Blocking H2A.Z Incorporation via Tip60 Inhibition Promotes Systems Consolidation of Fear Memory in Mice

Abstract

Memory formation is a protracted process that initially involves the hippocampus and becomes increasingly dependent on the cortex over time, but the mechanisms of this transfer are unclear. We recently showed that hippocampal depletion of the histone variant H2A.Z enhances both recent and remote memories, but the use of virally mediated depletion reduced H2A.Z levels throughout testing, making its temporally specific function unclear. Given the lack of drugs that target histone variants, we tested existing drugs for efficacy against H2A.Z based on their targeting of known H2A.Z regulators. The Tip60 (part of H2A.Z deposition complex) inhibitor Nu9056 reduced H2A.Z binding, whereas the histone deacetylase (HDAC) inhibitor Trichostatin-A increased H2A.Z acetylation without influencing total H2A.Z in cultured hippocampal neurons. Tip60 (but not HDAC) inhibition 23 h after learning enhanced remote (tested at 7 d) and not recent (tested at 24 h) contextual fear memory in mice. In contrast, Tip60 inhibition 30 d after learning impaired recall of remote memory after 1 h, but protected the memory from further decline 24 h later. These data provide the first evidence of a delayed postlearning role for histone variants in supporting memory transfer during systems consolidation.

Sex-specific effects of the histone variant H2A.Z on fear memory, stress-enhanced fear learning and hypersensitivity to pain

“…3). Notably, H2A.Z binding in males can be stably altered after fear conditioning 22 , indicating that experience-induced alterations in H2A.Z may mediate adaptations and responses to subsequent events. Some evidence shows that stress exposure has opposite effects on histone modifications in the frontal cortex and hippocampus of males and females 31 , suggesting that unique adaptations to stress can produce unique responses to subsequent fear-related learning in each sex.…”

“…Epigenetic modifications emerged as strong candidate mechanisms for understanding stable behavioral adaptations, such as PTSD, because of their potential to persist over long periods of time and their vital role in the maintenance of enduring fear memories [20][21][22][23] . Indeed, epigenetic mechanisms are involved in adapting to stressors and are emerging as regulators of pain responses in human patients 24 , making them especially promising as potential links between fear memory, PTSD, and pain.…”

“…Moreover, histone variants form an important part of the histone code through interactions with other epigenetic modifications, including a well characterized exclusion of H2A.Z from methylated DNA in nonneuronal cells 40,42 , indicating that a comprehensive understanding of epigenetic regulation of neural plasticity necessitates the study of histone variants. In contrast to post-translational modifications, which tend to be short lasting 21,43 , histone H2A.Z incorporation into nucleosomes is stably altered after fear learning 22 , suggesting that histone H2A.Z may also be relevant for regulating stable phenomena, such as PTSD.…”

An Emerging Role of m6A in Memory: A Case for Translational Priming

“…While the view of ‘open vs closed’ states is still a vital mechanism of epigenetic priming, work diagramming ‘poised’ or ‘bivalent’ promoters have provided an easier framework to understand epigenetic priming. Bivalent promoters are promoters that contain both a positive and repressive transcriptional mark on the appropriate histone at the same time [ 69 ]. Although these genes are turned ‘off’, the promoter resolves into an active state in response to an appropriate stimulus.…”

“…Although these genes are turned ‘off’, the promoter resolves into an active state in response to an appropriate stimulus. If the promoter is resolved in the positive direction, the locus starts transcription faster than if it was not primed initially [ 69 ]. While the purpose of this review is not epigenetic priming, the concept of priming is vital to our understanding of translational priming.…”