Importin Alpha Subtypes Determine Differential Transcription Factor Localization in Embryonic Stem Cells Maintenance

Yasuhara, Noriko; Yamagishi, Ryosuke; Arai, Yoshiyuki; Mehmood, Rashid; Kimoto, Chihiro; Fujita, Tomoya; Touma, Kenichi; Kaneko, Azumi; Kamikawa, Yasunao; Moriyama, Tetsuji; Yanagida, Toshio; Kaneko, Hiroki; Yoneda, Yoshihiro

doi:10.1016/j.devcel.2013.06.022

Cited by 61 publications

(74 citation statements)

References 47 publications

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“…Our investigation also reveals that sustained ectopic expression of Kpna2 during ESC differentiation suppressed circadian clock development. Recently it has been reported that subtype switching of Importin-α2 (KPNA2) expression to α1 (KPNA1) is observed during differentiation of ESCs, and Importin-α2 negatively regulates the nuclear import of Oct6 to inhibit ESC differentiation (29,30). Our study revealed that KPNA2 acts as a key factor controlling circadian clock development.…”

Section: Discussionmentioning

confidence: 52%

“…Through the analysis of our mutant ESC models, we found the misregulation of Kpna2 expression, reported as one of the key factors regulating ESC differentiation (30), as a common factor affecting circadian clock development. In ESCs as well as the differentiated cells that failed to generate clock oscillation, significantly higher expression of Kpna2 gene was observed compared with cells with functional clock.…”

Section: Discussionmentioning

confidence: 98%

“…6A). The Kpna2 gene encodes the Importin-α2 protein known to regulate the nuclear translocation of transcription factors, and the switching of the expression of the Importin-α subtype from α2 to α1 is known to play an important role in ESC differentiation (29,30). Therefore, we first analyzed the ratio of Kpna expression in differentiated cells against ESCs.…”

Section: Kpna2 Functions As a Critical Factor Regulating Differentiatmentioning

confidence: 99%

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

Umemura

Koike

Matsumoto

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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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 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.T he circadian clock is an intrinsic time-keeping system that regulates essential physiological functions such as sleep/wake cycles, body temperature, and metabolism (1-3). In the mammalian clock system the central pacemaker resides in the suprachiasmatic nucleus of the hypothalamus, coordinating cell-autonomous molecular oscillators throughout the body to perform tissue-specific functions. The molecular oscillator consists of transcriptional/ translational feedback loops of clock genes. Two transcription factors, CLOCK and BMAL1, heterodimerize and transactivate core clock genes such as the Period (Per1, 2, 3), Cryptochrome (Cry1, 2), and Rev-Erbα genes via E-box regulatory elements. PER and CRY proteins, in turn, translocate into the nucleus to suppress CLOCK/BMAL1 activity, leading to cyclic expression of these clock genes (4-9). Furthermore, REV-ERBα negatively regulates Bmal1 transcription via the RORE promoter element, thus driving antiphasic expression patterns of Bmal1 (10, 11).Despite uncovering the emergence of the circadian rhythms that occur during development (12-14), the precise mechanism of circadian clock development in mammalian cells remains unclear. Recently it has been found that pluripotent ES cells (ESCs) do not display discernible circadian molecular oscillations, whereas in vitro-differentiated ESCs displayed robust circadian oscillations of reporter expression (15-17). Moreover, we also have shown that circadian oscillations were abolished when differentiated cells were reprogrammed to regain pluripotency by expression of reprogramming factors (Oct3/4, Sox2, Klf4, and c-Myc) (15). These results suggested that the emergence of the cell-autonomous circadian oscillator is coupled with cellular differentiation. Cellular differentiation, as well as reprogramming, results in global alterations of the transcriptional program and epi...

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 98%

Section: Kpna2 Functions As a Critical Factor Regulating Differentiatmentioning

confidence: 99%

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

Umemura

Koike

Matsumoto

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…from undifferentiated state into neural lineage for embryonic stem cells (Yasuhara et al 2013); hence, identification of KPNA2 binding partners may reveal how meiotic entry and exit is controlled in both sexes. Although total protein levels did not vary for the other KPNAs examined, their dynamic localisation patterns suggest changing roles at this time.…”

Section: Karyopherins In Oogenesismentioning

confidence: 99%

Changing expression and subcellular distribution of karyopherins during murine oogenesis

et al. 2015

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Mammalian oocyte growth and development is driven by a strict program of gene expression that relies on the timely presence of transcriptional regulators via nuclear pores. By targeting specific cargos for nucleo-cytoplasmic transport, karyopherin (KPN) proteins are key to the relocation of essential transcription factors and chromatin-remodelling factors into and out of the nucleus. Using multiple complementary techniques, here we establish that KPNA genes and proteins are dynamically expressed and relocalised throughout mouse oogenesis and folliculogenesis. Of the KPNAs examined (Kpna1, Kpna2, Kpna3, Kpna4, Kpna6, Kpna7, Kpnb1, Ipo5 and Xpo1), all were expressed in the embryonic ovary with up-regulation of protein levels concomitant with meiotic entry for KPNA2, accompanied by the redistribution of the cellular localisation of KPNA2 and XPO1. In contrast, postnatal folliculogenesis revealed significant up-regulation of Kpna1, Kpna2, Kpna4, Kpna6 and Ipo5 and down-regulation of Kpnb1, Kpna7 and Xpo1 at the primordial to primary follicle transition. KPNAs exhibited different localisation patterns in both oocytes and granulosa cells during folliculogenesis, with three KPNAs -KPNA1, KPNA2 and IPO5 -displaying marked enrichment in the nucleus by antral follicle stage. Remarkably, varied subcellular expression profiles were also identified in isolated pre-ovulatory oocytes with KPNAs KPNA2, KPNB1 and IPO5 detected in the cytoplasm and at the nuclear rim and XPO1 in cytoplasmic aggregates. Intriguingly, meiotic spindle staining was also observed for KPNB1 and XPO1 in meiosis II eggs, implying roles for KPNAs outside of nucleo-cytoplasmic transport. Thus, we propose that KPNAs, by targeting specific cargoes, are likely to be key regulators of oocyte development. Reproduction (2015) 150 485-496

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“…Additionally, it keeps differentiation linked factors, like OCT6, in the cytoplasm. Through this, a pluripotent state is retained (Yasuhara et al 2013 ). Importin α2 also keeps clock factors like PER1 and PER2 in the cytoplasm (Umemura et al 2014 ).…”

Section: Oscillation Of Core Clock Genes Upon Differentiation Of Embrmentioning

confidence: 99%

Circadian Rhythms in Stem Cell Biology and Function

Dierickx

Pré

Feyen

et al. 2015

Stem Cell Biology and Regenerative Medicine

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Importin Alpha Subtypes Determine Differential Transcription Factor Localization in Embryonic Stem Cells Maintenance

Cited by 61 publications

References 47 publications

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

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

Changing expression and subcellular distribution of karyopherins during murine oogenesis

Circadian Rhythms in Stem Cell Biology and Function

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