Age- and cell type- specific effects of histone variant H2BE in the brain

Transcription is regulated in part through histone proteins that bind DNA and control access to genes. Histones can be replaced with variant forms that are particularly critical in the brain and accumulate throughout lifespan. Recent findings defined the first broadly expressed H2B variant, H2BE, and demonstrated that it regulates chromatin structure, neuronal transcription, and mouse behavior. However, the role of H2BE in other cell types and its role throughout lifespan remain unknown. Here, we discovered that H2BE is enriched in astrocytes in the brain and accumulates with age in both astrocytes and neurons. Using single-nucleus RNA-sequencing, we demonstrate that H2BE promotes synaptic gene expression in neurons and astrocytes in young brains. Using microelectrode array recordings, we discovered that H2BE is required in both cell types for proper synaptic function. In aging brains, loss of H2BE similarly affects synaptic genes in neurons but also dampens some age-related transcriptional changes in both astrocytes and neurons. Lastly, behavioral testing demonstrates that H2BE loss disrupts long-term memory but improves working memory in aging mice. Together, these data provide novel links between histone variants, aging-related gene expression changes in both astrocytes and neurons, and memory.