The molecular clock protein Bmal1 regulates cell differentiation in mouse embryonic stem cells

Abstract

Mammals optimize their physiology to the light–dark cycle by synchronization of the master circadian clock in the brain with peripheral clocks in the rest of the tissues of the body. Circadian oscillations rely on a negative feedback loop exerted by the molecular clock that is composed by transcriptional activators Bmal1 and Clock, and their negative regulators Period and Cryptochrome. Components of the molecular clock are expressed during early development, but onset of robust circadian oscillations is only detected later during embryogenesis. Here, we have used naïve pluripotent mouse embryonic stem cells (mESCs) to study the role of Bmal1 during early development. We found that, compared to wild-type cells, Bmal1−/− mESCs express higher levels of Nanog protein and altered expression of pluripotency-associated signalling pathways. Importantly, Bmal1−/− mESCs display deficient multi-lineage cell differentiation capacity during the formation of teratomas and gastrula-like organoids. Overall, we reveal that Bmal1 regulates pluripotent cell differentiation and propose that the molecular clock is an hitherto unrecognized regulator of mammalian development.

BMAL1 coordinates energy metabolism and differentiation of pluripotent stem cells

“…In line with this, we show that the absence of BMAL1 affects EB formation and gastrulation, using two independent differentiation in vitro organoid systems. Similar conclusions were drawn from an independently performed study, which recently came to our attention (Gallardo et al, 2020). Mechanistically, we find that depletion of Bmal1 induces a shift in the basal metabolism of pluripotent cells involving an increase OXPHOS activity accompanied by augmented mtROS species production.…”

Circadian rhythms in bipolar disorder patient-derived neurons predict lithium response: preliminary studies

“…Previous neuronal models of BD have implicated neurodevelopmental pathways 50 , but the interaction between development and the circadian clock remains poorly described. In mice, the clock is active in embryonic stem cells and developmentally regulated, with Bmal1 contributing to stem cell differentiation 51 , 52 . However, no studies have investigated clock genes across development in human neuronal models.…”

A transcriptomics-guided drug target discovery strategy identifies novel receptor ligands for lung regeneration

“…Intriguingly, we identified circadian clock signaling as being significantly repressed in the alveolar epithelial progenitors derived from mice exposed to CS, which could be improved by either misoprostol or iloprost treatment. Circadian rhythms [40][41][42][43] are normally generated and regulated by clock genes, including BMAL1 (ARNTL1) and CLOCK encoding activators, period (PER1-3) and cryptochrome genes (CRY1-2) that encode repressors, and the nuclear receptors Rev-erb (NR1D1 and NR1D2) and RORA which constitute secondary regulatory loops. These core clock genes not only activate or repress a cell-autonomous clock, but also regulate the clock-controlled genes (CCGs) , thus interacting with other molecular signaling pathways.…”