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

Abstract

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.

Histone H1x in mouse ventral hippocampus associates with, but does not cause behavioral adaptations to stress

“…Although our viral vector did successfully increase intra-vHipp levels of H1x protein, we did not find any behavioral consequences of vHipp H1x OE, regardless of an animal's level of stress exposure or its determined stress-related phenotype. We feel this is important to report, since there is a robust body of literature that has identified brain molecular profiles that diverge across stress-resilient and stress-susceptible mice, and have often described perturbations of these brain processes as causally controlling the emergence of stress-related behaviors [7][8][9][10][25][26][27][28][29], including in the vHipp [30][31][32][33][34][35][36]. Despite these past insights into the brain molecular mechanisms that control stress response, it is reasonable that not all molecular profiles correlated with stress response are singularly sufficient to drive the emergence of stress-related behaviors.…”

Histone H1x in mouse ventral hippocampus correlates with, but does not cause behavioral adaptations to stress

“…Previously, multiple core histone variants have been documented to play critical roles in many behavioral processes, including the fear conditioning paradigm applied in this study 28,35,37,47,48 , with particular attention being paid to histone crosstalk between different PTMs on specific histone variants influencing learning and memory 49,50 . A prominent example of this histone crosstalk involves H1x specifically altering H3 lysine methylation, in turn altering gene expression of multiple immune related genes 27,51 .…”

Roles of Histone H2A Variants in Cancer Development, Prognosis, and Treatment

“…MacroH2A not only has a well-known function in gene repression, it also has a dual function in signal-induced gene activation. One of the best examples is macroH2A1, but not macroH2A2, regulates memory processing and formation, which its occupancy in hippocampus is dynamically modified in order to promote learning-induced transcriptional activation, especially in upregulated genes following training [ 149 ].…”