The histone chaperone Anp32e regulates memory formation, transcription, and dendritic morphology by regulating steady-state H2A.Z binding in neurons

Stefanelli, Gilda; Makowski, Claire E.; Brimble, Mark A.; Hall, Meaghan; Reda, Anas; Creighton, Samantha D.; Leonetti, Amanda M.; McLean, Timothy A. B.; Zakaria, Jacqueline M.; Baumbach, Jennet L.; Greer, Celeste B.; Davidoff, Andrew M.; Walters, Brandon J.; Murphy, Patrick J.; Zovkic, Iva B.

doi:10.1016/j.celrep.2021.109551

Cited by 10 publications

(5 citation statements)

References 31 publications

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“…This is supported further by the observation that the genomic sites where ANP32e is located do not necessarily overlap with sites where H2A.Z abundance changes after depletion of ANP32e. 13 , 17 Another study reported that co-depletion of ANP32e and H2A.Z increased H2A.Z content in chromatin despite a significant decrease in the overall protein levels of H2A.Z. 17 Based on our results, this suggests that depletion of ANP32e could cause a shift from soluble to chromatin-bound H2A.Z through the function of ANP32e as a molecular chaperone.…”

Section: Discussionsupporting

confidence: 56%

“… 13 , 17 Another study reported that co-depletion of ANP32e and H2A.Z increased H2A.Z content in chromatin despite a significant decrease in the overall protein levels of H2A.Z. 17 Based on our results, this suggests that depletion of ANP32e could cause a shift from soluble to chromatin-bound H2A.Z through the function of ANP32e as a molecular chaperone. The exact mechanism by which ANP32e regulates H2A.Z protein stability in U2OS cells remains to be determined, however ANP32e may protect H2A.Z from proteasomal degradation through PP2A inhibition.…”

Section: Discussionsupporting

confidence: 56%

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ANP32e Binds Histone H2A.Z in a Cell Cycle-Dependent Manner and Regulates Its Protein Stability in the Cytoplasm

Dijkwel,

Hart-Smith,

Kurscheid

et al. 2024

Molecular and Cellular Biology

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ANP32e, a chaperone of H2A.Z, is receiving increasing attention because of its association with cancer growth and progression. An unanswered question is whether ANP32e regulates H2A.Z dynamics during the cell cycle; this could have clear implications for the proliferation of cancer cells. We confirmed that ANP32e regulates the growth of human U2OS cancer cells and preferentially interacts with H2A.Z during the G1 phase of the cell cycle. Unexpectedly, ANP32e does not mediate the removal of H2A.Z from chromatin, is not a stable component of the p400 remodeling complex and is not strongly associated with chromatin. Instead, most ANP32e is in the cytoplasm. Here, ANP32e preferentially interacts with H2A.Z in the G1 phase in response to an increase in H2A.Z protein abundance and regulates its protein stability. This G1-specific interaction was also observed in the nucleoplasm but was unrelated to any change in H2A.Z abundance. These results challenge the idea that ANP32e regulates the abundance of H2A.Z in chromatin as part of a chromatin remodeling complex. We propose that ANP32e is a molecular chaperone that maintains the soluble pool of H2A.Z by regulating its protein stability and acting as a buffer in response to cell cycle-dependent changes in H2A.Z abundance.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionsupporting

confidence: 56%

ANP32e Binds Histone H2A.Z in a Cell Cycle-Dependent Manner and Regulates Its Protein Stability in the Cytoplasm

Dijkwel,

Hart-Smith,

Kurscheid

et al. 2024

Molecular and Cellular Biology

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“…This difference in dynamics is consistent with evidence that mH2A2 is the predominant barrier in somatic cell reprogramming 17 , and hence it might be more resistant to losing its deposition in response to signalling events. Prior evidence shows that the histone variants H2A.Z and H3.3 that affect memory formation both exhibit activity-mediated turnover 4,5,7,35 , suggesting that the lack of mH2A2 dynamics in the present study may be associated with its weaker role in memory than the dynamically regulated histone mH2A1.…”

Section: Mh2a1 Depletion Blocks Learning-induced Gene Expressionmentioning

confidence: 55%

“…Several studies have demonstrated that histones H2A.Z and H3.3 play a role in memory and are dynamically regulated by neural activity and learning 4,5,7,35 , suggesting that histone dynamics may be critical for memory. Data from the present study extend these findings to mH2A by showing that mH2A1 is more dynamic of the two isoforms and has a stronger role in memory than mH2A2.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

Self Cite

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Histone variants H2A.Z and H3.3 are epigenetic regulators of memory, but roles of other variants are not well characterized. macroH2A (mH2A) is a structurally unique histone that contains a globular macrodomain connected to the histone region by an unstructured linker. Here we assessed if mH2A regulates memory and if this role varies for the two mH2A-encoding genes, H2afy (mH2A1) and H2afy2 (mH2A2). We show that fear memory is impaired in mH2A1, but not in mH2A2-deficient mice, whereas both groups were impaired in a non-aversive spatial memory task. However, impairment was larger for mH2A1- deficient mice, indicating a preferential role for mH2A1 over mH2A2 in memory. Accordingly, mH2A1 depletion in the mouse hippocampus resulted in more extensive transcriptional de-repression compared to mH2A2 depletion. mH2A1-depleted mice failed to induce a normal transcriptional response to fear conditioning, suggesting that mH2A1 depletion impairs memory by altering transcription. Using chromatin immunoprecipitation (ChIP) sequencing, we found that both mH2A proteins are enriched on transcriptionally repressed genes, but only mH2A1 occupancy was dynamically modified during learning, displaying reduced occupancy on upregulated genes after training. These data identify mH2A as a regulator of memory and suggest that mH2A1 supports memory by repressing spurious transcription and promoting learning-induced transcriptional activation.

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“…ANP32e is an H2A.Z-specific histone chaperone that has been suggested to remove H2A.Z from chromatin in cooperation with the p400–TIP60 [ 119 ] and INO80 [ 120 ] chromatin remodeling complexes. While ANP32e has been shown to remove H2A.Z from chromatin in mouse embryonic fibroblasts (MEFs) [ 119 ] and reduce steady-state chromatin levels of H2A.Z in mouse neurons to regulate memory formation [ 121 ], ANP32e-knockout mice develop normally [ 122 ]. ANP32e deletion in MEFs causes upregulation of differentiation genes [ 123 ] and approximately 30% of ANP32e-knockout zebrafish survive to adulthood [ 42 ].…”

Section: Complexes That Regulate Genome Localization Of H2az During D...mentioning

confidence: 99%

The Role of the Histone Variant H2A.Z in Metazoan Development

Dijkwel

Tremethick

2022

JDB

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During the emergence and radiation of complex multicellular eukaryotes from unicellular ancestors, transcriptional systems evolved by becoming more complex to provide the basis for this morphological diversity. The way eukaryotic genomes are packaged into a highly complex structure, known as chromatin, underpins this evolution of transcriptional regulation. Chromatin structure is controlled by a variety of different epigenetic mechanisms, including the major mechanism for altering the biochemical makeup of the nucleosome by replacing core histones with their variant forms. The histone H2A variant H2A.Z is particularly important in early metazoan development because, without it, embryos cease to develop and die. However, H2A.Z is also required for many differentiation steps beyond the stage that H2A.Z-knockout embryos die. H2A.Z can facilitate the activation and repression of genes that are important for pluripotency and differentiation, and acts through a variety of different molecular mechanisms that depend upon its modification status, its interaction with histone and nonhistone partners, and where it is deposited within the genome. In this review, we discuss the current knowledge about the different mechanisms by which H2A.Z regulates chromatin function at various developmental stages and the chromatin remodeling complexes that determine when and where H2A.Z is deposited.

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The histone chaperone Anp32e regulates memory formation, transcription, and dendritic morphology by regulating steady-state H2A.Z binding in neurons

Cited by 10 publications

References 31 publications

ANP32e Binds Histone H2A.Z in a Cell Cycle-Dependent Manner and Regulates Its Protein Stability in the Cytoplasm

ANP32e Binds Histone H2A.Z in a Cell Cycle-Dependent Manner and Regulates Its Protein Stability in the Cytoplasm

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

The Role of the Histone Variant H2A.Z in Metazoan Development

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