Age and cell type specific specific effects of histone variant H2BE in the brain [Intact_RNAseq]

Transcription is regulated in part through histone proteins that complex with DNA and control access to genes. Histones can be replaced with variant forms that are particularly critical in the brain and accumulate throughout lifespan. Recently, we 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 highly expressed in astrocytes as well as neurons and accumulates with age in both cell types. Using single-nucleus RNA-sequencing, we demonstrate that loss of H2BE robustly affects gene expression in both astrocytes and neurons, with divergent effects in young and aging brains. Interestingly, loss of H2BE in young brains causes similar gene expression changes as aging and some effects of aging are reversed with H2BE loss. 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. Overall design: Cortical nuclei were isolated from P0, P14, and P28 male mouse pups. Mice were heterozygous for the CAG-Sun1/sfGFP nuclear marker and NEX-cre. Cre-expressing cortical nuclei were isolated using isolation of nuclei tagged in specific cells type (INTACT) immunpurification method. (n = 4 biological replicates per age)