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Transcriptional Program of Kpna2 (Importin-alpha2) Regulates Cellular Differentiation-Coupled Circadian Clock Development in Mammalian Cells

ABSTRACT: The circadian clock in mammalian cells is cell-autonomously generated during the cellular differentiation process, but the underlying mechanisms are not understood. Here we show that perturbation of transcriptional program by constitutive expression of c-Myc and Dnmt1 ablation disrupts the differentiation-coupled emergence of the clock from mouse embryonic stem cells (ESCs). Using these model ESCs, 484 genes are identified by global gene expression analysis as correlating factors with differentiation-coupled circadian clock development. Among them, we find the misregulation of Kpna2 (Importin-alpha2) during the differentiation of the c-Myc over-expressed and Dnmt1-/- ESCs, in which sustaining cytoplasmic accumulation of PER proteins is observed. Moreover, constitutive expression of Kpna2 during the differentiation culture of ESCs significantly impairs clock development and KPNA2 facilitates cytoplasmic localization of PER1/2. These results suggest that the programmed gene expression network regulates the differentiation-coupled circadian clock development in mammalian cells, at least in part via post-transcriptional regulation of clock proteins.

ORGANISM(S): Mus musculus

PROVIDER: GSE61184 | GEO | 2014/11/13

SECONDARY ACCESSION(S): PRJNA260445

REPOSITORIES: GEO

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Transcriptional Program of Kpna2 (Importin-α2) Regulates Cellular Differentiation-Coupled Circadian Clock Development in Mammalian Cells

Project description:The circadian clock in mammalian cells is cell-autonomously generated during the cellular differentiation process, but the underlying mechanisms are not understood. Here we show that perturbation of transcriptional program by constitutive expression of c-Myc and Dnmt1 ablation disrupts the differentiation-coupled emergence of the clock from mouse embryonic stem cells (ESCs). Using these model ESCs, 484 genes are identified by global gene expression analysis as factors correlated with differentiation-coupled circadian clock development. Among them, we find the misregulation of Kpna2 (Importin-α2) during the differentiation of the c-Myc over-expressed and Dnmt1-/- ESCs, in which sustained cytoplasmic accumulation of PER proteins is observed. Moreover, constitutive expression of Kpna2 during the differentiation culture of ESCs significantly impairs clock development and KPNA2 facilitates cytoplasmic localization of PER1/2. These results suggest that the programmed gene expression network regulates the differentiation-coupled circadian clock development in mammalian cells, at least in part via post-transcriptional regulation of clock proteins.

2014-11-13 | GSE61096 | GEO

Mus musculus

Project description:Transcriptional Program of Kpna2 (Importin-alpha2) Regulates Cellular Differentiation-Coupled Circadian Clock Development in Mammalian Cells

| PRJNA260445 | ENA

Mus musculus

Project description:Transcriptional Program of Kpna2 (Importin-α2) Regulates Cellular Differentiation-Coupled Circadian Clock Development in Mammalian Cells

| PRJNA260215 | ENA

Development of human cartilage circadian rhythm in a stem cell-chondrogenesis model

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Disruption of circadian clockwork in in vivo reprogramming-induced mouse kidney tumors

Project description:The circadian clock, which regulates cellular physiology, such as energy metabolism, resides in each cell level throughout the body. Recently, it has been elucidated that the cellular circadian clock is closely linked with cellular differentiation. Moreover, the misregulation of cellular differentiation in mouse embryonic stem cells (ESCs) induced abnormally differentiated cells with impaired circadian clock oscillation, concomitant with the post-transcriptional suppression of CLOCK proteins. Here, we show that the circadian molecular oscillation is disrupted in dysdifferentiation-mediated mouse kidney tumors induced by partial in vivo reprogramming, resembling Wilms tumors. The expression of CLOCK protein was dramatically reduced in the tumor cells despite the Clock mRNA expression. We also showed that a similar loss of CLOCK was observed in human Wilms tumors, suggesting that the circadian molecular clockwork may be disrupted in dysdifferentiation-mediated embryonal tumors such as Wilms tumors, similar to the in vivo reprogramming induced mouse kidney tumors. These results support our previous reports and may provide a novel viewpoint for understanding the pathophysiological nature of cancers through the correlation between cellular differentiation and circadian clock.

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BMAL1 coordinates energy metabolism and differentiation of pluripotent stem cells.

Project description:In spite of lacking circadian rhythms, several master clock regulators are readily expressed in embryonic stem cells (ESCs). In particular, the role of Brain and Muscle ARNT-Like 1 (Bmal1, also known as Arntl) remains to be addressed. Here, we generated Bmal1 CRISPR/cas9 knock-out ESCs to elucidate the role of BMAL1 in pluripotency maintenance and differentiation. Our findings indicate that although BMAL1 is dispensable for ESC maintenance, it is required for proper differentiation. Moreover, we find that Bmal1 participates in the transcriptional regulation of lineage specification programs during differentiation and gastrulation in vitro. In particular, loss-of-function of Bmal1 changes the metabolic state of ESCs by promoting more oxidation at the expense of glycolysis. Our data points to a circadian clock-independent function of BMAL1 during early developmental stages, and will help in the understanding of the mechanisms that control exit from pluripotency and early cell-fate decisions.

2020-04-13 | GSE133908 | GEO

Polysome profiling in Arabidopsis thaliana over a 24-hour diurnal cycle

Project description:Circadian control of gene expression has been established in plants at the transcriptional level, but relatively little is known about circadian control of translation. We used polysome profiling to characterize regulation of transcription and translation over a 24-hour diurnal cycle in Arabidopsis, both in wild type and in plants with a disrupted clock due to constitutive overexpression of the CIRCADIAN CLOCK ASSOCIATED 1 gene (CCA1-ox, AGI AT2G46830).

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2015-10-15 | GSE61896 | GEO

Transcript levels in Arabidopsis thaliana over a 24-hour diurnal cycle

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Polysome profiling in CIRCADIAN CLOCK ASSOCIATED 1-overexpressing (CCA1-ox) Arabidopsis thaliana over a 24-hour diurnal cycle

2015-10-15 | GSE61898 | GEO