Sexual dimorphism in the response to chronic circadian misalignment (ChIP-Seq). Sexual dimorphism in the response to chronic circadian misalignment (ChIP-Seq)

Longitudinal studies associate shiftwork with cardiometabolic disorders but do not establish causation nor elucidate mechanisms of disease. We developed a mouse model based on shiftwork schedules to study circadian misalignment in both sexes, where misaligned mice undergo an 8-hour phase advance every week for 15 weeks. Behavioral and transcriptional rhythmicity were preserved in female mice despite exposure to misalignment. Females were protected against the cardiometabolic impact of circadian disruption seen in males. The liver transcriptome and proteome revealed discordant pathway perturbations between the sexes. Tissue-level changes were accompanied by gut microbiome dysbiosis only in male mice. In the UK biobank, female shiftworkers showed stronger circadian rhythmicity in activity and a lower incidence of metabolic syndrome than males. Thus we show that female mice are resilient to chronic circadian misalignment, and that these differences are conserved in humans. Overall design: Liver BMAL1-DNA interaction profiles of male control, male misaligned, female control and female misaligned mice taken at two time points, ZT0 and ZT12. One biological replicate was analyzed per timepoint per group.

纵向研究已将轮班工作与心血管代谢疾病（cardiometabolic disorders）建立关联，但尚未明确二者的因果关系，亦未阐明疾病发生的具体机制。
本研究基于轮班工作排班构建了小鼠模型，用于探究不同性别的昼夜节律紊乱（circadian misalignment）情况：该模型中，节律紊乱小鼠每周会经历8小时的相位前移，持续15周。
尽管暴露于节律紊乱环境，雌性小鼠仍保留了行为与转录水平的节律性。
雌性小鼠可免受雄性小鼠中观察到的、由昼夜节律紊乱引发的心血管代谢损伤。
肝脏转录组（transcriptome）与蛋白质组（proteome）分析显示，不同性别间的通路扰动模式存在显著差异。
仅在雄性小鼠中，组织水平的变化伴随出现了肠道菌群失调（gut microbiome dysbiosis）。
在英国生物银行（UK Biobank）队列中，女性轮班工作者的活动节律性更强，且代谢综合征（metabolic syndrome）的发病率低于男性。
综上，本研究证实雌性小鼠可耐受慢性昼夜节律紊乱，且上述性别差异在人类中同样保守存在。
整体实验设计：采集雄性对照组、雄性节律紊乱组、雌性对照组及雌性节律紊乱组小鼠的肝脏BMAL1-DNA结合谱，采样时间点为ZT0与ZT12。每组每个时间点均设置1个生物学重复进行分析。