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

30 Citations (Scopus)

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

Fingerprint

Karyopherins
Circadian Clocks
Methyltransferases
Gene Expression
Gene Regulatory Networks
DNA
Statistical Factor Analysis
Proteins
Transcription Factors
Genes

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Transcriptional program of Kpna2/Importin-α2 regulates cellular differentiation-coupled circadian clock development in mammalian cells. / Umemura, Yasuhiro; Koike, Nobuya; Matsumoto, Tsuguhiro; Yoo, Seung Hee; Chen, Zheng; Yasuhara, Noriko; Takahashi, Joseph S.; Yagita, Kazuhiro.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 47, 25.11.2014, p. E5039-E5048.

Research output: Contribution to journalArticle

Umemura, Yasuhiro ; Koike, Nobuya ; Matsumoto, Tsuguhiro ; Yoo, Seung Hee ; Chen, Zheng ; Yasuhara, Noriko ; Takahashi, Joseph S. ; Yagita, Kazuhiro. / Transcriptional program of Kpna2/Importin-α2 regulates cellular differentiation-coupled circadian clock development in mammalian cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 47. pp. E5039-E5048.
@article{734ea56e343946bf987dc766c5ce7fad,
title = "Transcriptional program of Kpna2/Importin-α2 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. 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.",
keywords = "C-Myc, Cellular differentiation, Circadian clock, Dnmt1, Kpna2 (Importin-α2)",
author = "Yasuhiro Umemura and Nobuya Koike and Tsuguhiro Matsumoto and Yoo, {Seung Hee} and Zheng Chen and Noriko Yasuhara and Takahashi, {Joseph S.} and Kazuhiro Yagita",
year = "2014",
month = "11",
day = "25",
doi = "10.1073/pnas.1419272111",
language = "English (US)",
volume = "111",
pages = "E5039--E5048",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "47",

}

TY - JOUR

T1 - Transcriptional program of Kpna2/Importin-α2 regulates cellular differentiation-coupled circadian clock development in mammalian cells

AU - Umemura, Yasuhiro

AU - Koike, Nobuya

AU - Matsumoto, Tsuguhiro

AU - Yoo, Seung Hee

AU - Chen, Zheng

AU - Yasuhara, Noriko

AU - Takahashi, Joseph S.

AU - Yagita, Kazuhiro

PY - 2014/11/25

Y1 - 2014/11/25

N2 - 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.

AB - 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.

KW - C-Myc

KW - Cellular differentiation

KW - Circadian clock

KW - Dnmt1

KW - Kpna2 (Importin-α2)

UR - http://www.scopus.com/inward/record.url?scp=84912569226&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84912569226&partnerID=8YFLogxK

U2 - 10.1073/pnas.1419272111

DO - 10.1073/pnas.1419272111

M3 - Article

VL - 111

SP - E5039-E5048

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 47

ER -