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
C2 - 25389311
AN - SCOPUS:84912569226
SN - 0027-8424
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
IS - 47
ER -