What is it about?

Genetic studies support that the circadian clock regulates cell differentiation. Defects in circadian clock genes result in dysregulation of cell differentiation in immune, muscle, skin, and fat cells. However, how a perpetual daily clock with largely invariant periods can regulate a multi-day process such as cell differentiation was not understood. Our work addresses this fundamental question. We provide the first evidence that cells use a gating mechanism whereby a fast differentiation commitment step is triggered almost exclusively during the resting phase of the circadian clock. Markedly, we discovered that differentiation shows a bursting behavior, whereby only some progenitor cells commit to differentiate during each of multiple sequential rest phases of the clock. This is desirable since it keeps some progenitor cells available each day for differentiation rather than all being depleted at once. Another advantage of this gating mechanism is that glucocorticoids (cortisol in humans) and food stimuli, which can trigger progenitor cells to differentiate into fat cells, are highest during the day. Restricting differentiation commitment to occur only during the sleep period when these differentiation-inducing stimuli are low can help to suppress excessive fat cell production.

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Why is it important?

Our study shows that the cell-intrinsic circadian clock controls cell differentiation by restricting it to a short phase window each day when fat-cell differentiation inducing signals are low. Our results provide a molecular explanation for why dysregulated circadian rhythms may cause obesity by causing the differentiation commitment window to broaden, and thus making it overlap with fat-cell inducing signals.

Perspectives

We were able to answer the puzzling question how a perpetual daily clock control a much longer, multi-day differentiation process. Daily gating of differentiation occurs because cells can irreversibly commit to differentiate within only a few hours, which is faster than the rest phase and much faster than the overall multi-day differentiation process. Our finding also opens potential therapeutic strategies to enhance cell differentiation, and thus tissue regeneration, by timing when during the day drugs are administered.

Mary Teruel
Cornell University

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This page is a summary of: The circadian clock mediates daily bursts of cell differentiation by periodically restricting cell-differentiation commitment, Proceedings of the National Academy of Sciences, August 2022, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2204470119.
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