Transcriptional program of Kpna2/Importin-α2 regulates cellular differentiation-coupled circadian clock development in mammalian cells

Yasuhiro Umemura, Nobuya Koike, Tsuguhiro Matsumoto, Seung Hee Yoo, Zheng Chen, Noriko Yasuhara, Joseph S. Takahashi, Kazuhiro Yagita

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

The circadian clock in mammalian cells is cell-autonomously generated during the cellular differentiation process, but the underlying mechanisms are not understood. Herewe show that perturbation of the transcriptional program by constitutive expression of transcription factor c-Myc and DNA methyltransferase 1 (Dnmt1) ablation disrupts the differentiation-coupled emergence of the clock from mouse 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-overexpressed 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 posttranscriptional regulation of clock proteins.

Original languageEnglish (US)
Pages (from-to)E5039-E5048
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number47
DOIs
StatePublished - Nov 25 2014

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Keywords

  • C-Myc
  • Cellular differentiation
  • Circadian clock
  • Dnmt1
  • Kpna2 (Importin-α2)

ASJC Scopus subject areas

  • General

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