Aging Differentially Alters the Transcriptome and Landscape of Chromatin Accessibility in the Male and Female Mouse Hippocampus [RNA-Seq 2]

Long-term memory formation is dependent on gene expression changes in the hippocampal region of the brain. Aging-related memory impairments and incidence of pathological memory disorders such as Alzheimer's disease differ between males and females, and yet little is known about how aging-related changes to the transcriptome and chromatin environment differs between sexes in the hippocampus. To investigate this question, we compared the chromatin accessibility landscape and gene expression/alternative splicing pattern of young adult and aged mouse hippocampus of both males and females using ATAC-seq and RNA-seq. We detected significant aging-dependent changes in the expression of genes involved in immune response, cell adhesion, and synaptic function, and aging-dependent changes in the alternative splicing of myelin sheath genes. We found significant sex-bias in the expression and alternative splicing of hundreds of genes, including aging-dependent female-biased expression of myelin sheath genes and aging-dependent male-biased expression of genes involved in synaptic activity. Aging was associated with increased chromatin accessibility in both male and female hippocampus, especially in repetitive elements, and with an increase in LINE1 transcription. We detected significant sex-bias in chromatin accessibility in both autosomes and the X chromosome, with male-biased accessibility enriched at promoters and CpG-rich regions. Overall, sex differences in both gene expression and chromatin accessibility were amplified with aging, revealing that although some aspects of hippocampal aging are sex-independent, underlying sex differences in gene expression and chromatin dynamics in aging may shed light on sex differences in aging-related and pathological memory loss. RNA-Seq from hippocampus of young adult (10 week) or aged (80 week) male and female mice. Four biological replicates/group were sequenced, for a total of 16 samples.长时记忆的形成依赖于大脑海马体的基因表达改变。衰老相关的记忆损伤以及阿尔茨海默病（Alzheimer's disease）等病理性记忆障碍的发病率存在性别差异，但目前对于海马体中转录组和染色质微环境的衰老相关变化在不同性别间的差异机制仍知之甚少。为探究这一科学问题，本研究利用ATAC-seq（转座酶可及性测序）与RNA-seq（RNA测序）技术，比较了不同性别年轻成年与衰老小鼠的海马体染色质可及性图谱、基因表达及可变剪接模式。本研究检测到免疫应答、细胞黏附以及突触功能相关基因的表达存在显著的衰老依赖性变化，同时髓鞘基因的可变剪接也呈现衰老依赖性改变。本研究还发现数百个基因的表达与可变剪接存在显著的性别偏向性，其中包括髓鞘基因呈现衰老依赖性的雌性偏向表达，以及突触活动相关基因呈现衰老依赖性的雄性偏向表达。衰老与雌雄小鼠海马体的染色质可及性升高相关，尤其是在重复序列区域，同时伴随着LINE1（长散在核元件1）转录水平的升高。本研究在常染色体与X染色体中均检测到染色质可及性存在显著的性别偏向性，其中雄性偏向的可及性区域富集于启动子及CpG富集区域。总体而言，基因表达与染色质可及性的性别差异随衰老进程被进一步放大。这表明尽管海马体衰老的部分特征不依赖于性别，但衰老过程中基因表达与染色质动态变化的潜在性别差异，或可为揭示衰老相关及病理性记忆丧失的性别差异提供新的思路。本数据集的测序样本来自不同性别年轻成年（10周龄）或衰老（80周龄）小鼠的海马体，每组设置4个生物学重复，共获得16个测序样本。