Department of Biochemistry, Weill Cornell Medical College of Cornell University, New York, NY 10065.
The Ira & Gale Drukier Institute of Children's Health, Weill Cornell Medical College of Cornell University, New York, NY 10065.
Proc Natl Acad Sci U S A. 2022 Aug 16;119(33):e2204470119. doi: 10.1073/pnas.2204470119. Epub 2022 Aug 8.
Most mammalian cells have an intrinsic circadian clock that coordinates metabolic activity with the daily rest and wake cycle. The circadian clock is known to regulate cell differentiation, but how continuous daily oscillations of the internal clock can control a much longer, multiday differentiation process is not known. Here, we simultaneously monitor circadian clock and adipocyte-differentiation progression live in single cells. Strikingly, we find a bursting behavior in the cell population whereby individual preadipocytes commit to differentiate primarily during a 12-h window each day, corresponding to the time of rest. Daily gating occurs because cells irreversibly commit to differentiate within only a few hours, which is much faster than the rest phase and the overall multiday differentiation process. The daily bursts in differentiation commitment result from a differentiation-stimulus driven variable and slow increase in expression of PPARG, the master regulator of adipogenesis, overlaid with circadian boosts in PPARG expression driven by fast, clock-driven PPARG regulators such as CEBPA. Our finding of daily bursts in cell differentiation only during the circadian cycle phase corresponding to evening in humans is broadly relevant, given that most differentiating somatic cells are regulated by the circadian clock. Having a restricted time each day when differentiation occurs may open therapeutic strategies to use timed treatment relative to the clock to promote tissue regeneration.
大多数哺乳动物细胞都有内在的生物钟，它将代谢活动与日常的休息和唤醒周期协调起来。生物钟被认为可以调节细胞分化，但内部时钟的连续日常波动如何能够控制一个更长的、多日的分化过程尚不清楚。在这里，我们同时在单细胞中实时监测生物钟和脂肪细胞分化的进展。引人注目的是，我们发现细胞群体中存在爆发行为，即个别前脂肪细胞主要在每天 12 小时的窗口内承诺分化，这对应于休息时间。每日门控发生的原因是，细胞在短短几个小时内不可逆地承诺分化，这比休息时间和整个多日分化过程都要快得多。分化承诺的每日爆发是由分化刺激驱动的变量和缓慢增加的脂肪生成主调控因子 PPARG 的表达引起的，而这种表达是由快速的时钟驱动的 PPARG 调节剂如 CEBPA 驱动的生物钟增强所叠加的。我们发现，在与人类晚上相对应的生物钟周期阶段，细胞分化只会出现每日爆发，这具有广泛的相关性，因为大多数分化的体细胞都受到生物钟的调节。每天只有在特定时间发生分化，可能会为治疗策略提供机会，即根据生物钟安排时间进行治疗，以促进组织再生。
