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Histone variant macroH2A1 is a stronger regulator of hippocampal transcription and memory than macroH2A2 in mice

ABSTRACT: Our work and that of others (Zovkic et al 2014 Nature, Maze et al 2015 Neuron) recently established histone variants as novel regulators of memory, whereby enrichment of H2A.Z, a variant of histone H2A, impairs memory formation. However, H2A has several structurally and functionally distinct members whose function in memory has never been studied. macroH2A (mH2A) is of special interest because it has been implicated as a risk factor for neurodegenerative diseases, particularly Huntington’s (Hu et al 2011 PNAS), but its functional role in the brain is not known. Here, we conducted ChIP sequencing against macroH2A1 (mH2A1) and macroH2A2 (mH2A2) in the mouse hippocampus and showed that both proteins are enriched on transcriptionally silent genes, suggesting that mH2A has a repressive effect on transcription in the brain. However, only mH2A1 binding was dynamically reduced during learning, such that mH2A1 removal was associated with increased gene expression in response to fear conditioning. Additionally, viral vector mediated depletion of mH2A1 protein resulted in extensive dysregulation of gene transcription, whereas mH2A2 depletion had minimal transcriptional consequences. To determine if these differential downstream transcriptomes are functionally relevant, we showed that mH2A1, but not mH2A2 depletion resulted in impaired fear memory. These results suggest that mH2A1 is required for memory and that its dynamic removal during learning promotes training-induced gene expression. In concert with our prior evidence for a suppressive effect of H2A.Z on memory, these data suggest that unique H2A variants have distinct effects on memory formation and as such, implicate altered nucleosome composition as a novel regulator of neuroplasticity.

ORGANISM(S): Mus musculus

PROVIDER: GSE147445 | GEO | 2022/05/24

REPOSITORIES: GEO

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Project description:The mechanisms underlying age-associated memory impairment are not well understood. We have shown that the onset of memory disturbances in the aging brain is associated with altered hippocampal chromatin plasticity. During learning, aged mice display a specific deregulation of histone H4 lysine 12 (H4K12) acetylation. To analyze if deregulated H4K12 acetylation impacts on learning-induced gene-expression required for memory consolidation we performed a high-density oligonucleotide microarray to compare the entire hippocampal gene-expression profile of 3 and 16-month-old mice during memory consolidation. In order to identify genes differentially regulated between 3- and 16-month old mice upon fear conditioning we subjected 3- and 16-month old mice to fear conditioning (4 mice each group, total 8 mice) . Mice of the same age that were handled but not subjected to any of the employed behavior paradigms served as control (4 mice 3-month old and 4 mice 16-month old, total 8 mice). During fear conditioning mice are subjected to a novel context followed by a mild electric foot-shock (context-shock exposure). In order to identify genes that are differentially regulated upon fear conditioning and are specific to associative learning we also tested the hippocampal gene-expression profile of 3-month old mice subjected to the same context-exposure that is not followed by a foot-shock (Context-exposure) (4 mice) or receive an immediate foot shock once they are placed in the context and only afterwards are allowed to explore the context (shock-context exposure) (4 mice). In order to identify genes that are regulated upon fear conditioning and are specific to associative learning we compared the hippocampal gene-expression profile of mice subjected to fear conditioning (context-shock), context or shock-context exposure regarding to their age-matched control mice (3 month old) mentioned above (control). Hippocampi from each mice were tested resulting to 24 samples which were separately hybridized (OneColor Array Design).

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Histone variant macroH2A1 is a stronger regulator of hippocampal transcription and memory than macroH2A2 in mice

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