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

Author:

Singh GurdeepORCID,Stefanelli Gilda,Narkaj Klotilda,Brimble Mark A.,Creighton Samantha D.,McLean Timothy A. B.,Hall Meaghan,Mitchnick Krista A.,Zakaria Jacqueline,Phung Thanh,Reda Anas,Leonetti Amanda M.,Monks Ashley,Ianov LaraORCID,Winters Boyer D.,Walters Brandon J.ORCID,Davidoff Andrew M.ORCID,Mitchell Jennifer A.ORCID,Zovkic Iva B.ORCID

Abstract

AbstractHistone 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.

Funder

Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada

Gouvernement du Canada | Canadian Institutes of Health Research

Publisher

Springer Science and Business Media LLC

Subject

General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)

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