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Development of the Circadian Core Machinery in Mammals
Journal Pre-proof Development of the Circadian Core Machinery in Mammals Yasuhiro Umemura, Kazuhiro Yagita PII:
S0022-2836(20)30035-8
DOI:
https://doi.org/10.1016/j.jmb.2019.11.026
Reference:
YJMBI 66400
To appear in:
Journal of Molecular Biology
Received Date: 15 October 2019 Revised Date:
26 November 2019
Accepted Date: 26 November 2019
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Development of the Circadian Core Machinery in Mammals
Yasuhiro Umemura and Kazuhiro Yagita*
Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kyoto, 602-8566, Japan
*
Correspondence author: Kazuhiro Yagita ([email protected])
Phone: +81-75-251-5313 Fax: +81-75-241-1499
Declarations of interest: none
Highlights Mammalian cell-autonomous circadian clock development is coupled with cellular differentiation. The circadian clock emerges gradually during ontogeny. The core clock proteins and genes may be in different states between normal rhythmic cells with circadian clock and non-rhythmic cells. Posttranscriptional suppression of CLOCK proteins is one of the key mechanisms of the circadian clock development.
Keywords (5) Cellular differentiation, posttranscriptional regulation, CLOCK, circadian rhythm, cellular circadian clock
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Abstract The emergence of circadian molecular oscillation is observed as a gradual process during the development in mammals. Pluripotent stem cell differentiation cultures recapitulate this process, whereas reprogramming into an undifferentiated state reverses it. These findings indicate that the circadian clock is tightly coupled to the state of cellular differentiation. The state of the circadian core machinery in non-rhythmic cells may be different from that in rhythmic cells. In this review, we describe the circadian rhythm development during ontogeny in mammals and focus on the molecular mechanisms that suppress circadian molecular oscillations during early development and in pluripotent stem cells. We also discuss the biological implications of repressing cellular circadian oscillation in non-rhythmic cells.
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Introduction The mammalian circadian clock regulates diverse physiological functions in the whole body, such as the sleep–wake cycle, hormone release, body temperature, and metabolism. The central pacemaker of the circadian clock is the suprachiasmatic nucleus (SCN) in the hypothalamus. The SCN tunes the peripheral tissue clocks in anticipation of the cyclic environmental changes of the rotating earth. Each organ and also each cell, in addition to cultured cell lines, are endowed with an intrinsic cellular circadian clock [1-4]. The molecular principle of the cellular circadian clock is driven by transcriptional/translational feedback loops (TTFLs) composed of a subset of circadian clock genes. At the core of the TTFLs are two transcriptional factors, BMAL1 (also called ARNTL) and CLOCK. BMAL1 and CLOCK form a heterodimer that actively works in the induction of gene transcription by binding to E-box enhancer elements. Their induced gene expression includes their negative regulators Period (Per1, 2, 3) and Cryptochrome (Cry1, 2). The core circadian clock proteins assemble into a larger than 1-MDa macromolecular complex, which include PER and CRY in the nucleus and cytoplasm [5]. Once the BMAL1–CLOCK heterodimer forms a complex with PER and CRY proteins, it loses its transactivation activity. PERs and CRYs are reported to inhibit the inducible gene expression by promoting the dissociation of the BMAL1–CLOCK heterodimers from DNA [6]. In addition, BMAL1–CLOCK heterodimers also induce the expression of Rev-erbα (Nr1d1) and Rev-erbβ (Nr1d2), whose proteins repress Bmal1 expression by binding to the RORE promoter element [7, 8]. This process accrues the delay in gene expression of the clock components, and this delay in the TTFLs leads to circadian rhythmicity. Other proteins are involved in the regulation of this process and have been featured in this special issue and other reviews [9, 10].
Circadian development during ontogenesis Although almost all somatic cells are equipped with an intrinsic circadian clock, it has been reported that some cell types, including zygotes, the early embryo, and germline cells, do not have a robust circadian clock [11-13]. In recent decades, a
3
gradual circadian development during ontogeny has been reported [14-17]. In the mouse, embryonic tissues, such as the heart and liver, show circadian rhythms at around E13–18 [18-21]. Although the mouse SCN at E13.5 displays no circadian oscillations, the circadian rhythm of the SCN develops at E14.5 [22]. Human circadian rhythms also emerge gradually. The circadian rhythm of body temperature emerges immediately after birth in full-term infants [23], followed by the hormonal circadian rhythms between 3 and 6 months of age [23], with the sleep–wake cycle becoming more stable after 6 weeks of life [24]. Interestingly, in zebrafish, the circadian molecular oscillation is developed within one day of fertilization [25]. The different circadian clock formation periods may be attributed to species-specific developmental processes.
Circadian clock development tightly coupled with cellular differentiation state Recently, it has been reported that, despite mouse pluripotent stem cells such as embryonic stem (ES) cells having no discernible circadian molecular oscillations of TTFLs, in vitro differentiation of ES cells presents a circadian oscillation of clock gene expression cell-autonomously [26, 27]. Reprogramming of somatic cells using Yamanaka factors (Oct3/4, Klf4, Sox2, and c-Myc) [28] to produce induced pluripotent stem (iPS) cells results in the disappearance of the established circadian rhythm, suggesting that the circadian clock development is tightly coupled with the cellular differentiation state (Figure 1) [26]. During cell differentiation, genome-wide epigenetic modifications occur, and lineage-specific gene regulatory networks are established. Each undifferentiated cell is considered to follow a lineage-specific pathway to differentiate adequately as described in Waddington’s epigenetic landscape [29]. Almost all differentiated cells ultimately establish the TTFLs of the core circadian clock. The core circadian clock gene network regulates the diverse lineage- and tissue-specific gene expression as a circadian output. Consequently, higher-order physiological functions are acquired in the whole body. For example, the circadian clock in the mouse embryonic heart gradually develops from E10 after organogenesis, and a circadian molecular oscillation is observed from E17
4
[30]. In young adults, clock-controlled heart-specific genes are expressed [31]. It is also considered that other tissues acquire a core circadian molecular oscillation during ontogeny, at which point clock-controlled tissue-specific output genes are expressed. It is still unknown how tissue-specific gene expression becomes under the control of the core circadian clock after cell differentiation. The regulation may be related to the several circadian regulation of mRNA transcripts. Circadian regulations reside not only in the process of transcription but also mRNA translation and modification such as ploy-A modification, RNA methylation, and RNA-editing [32-34]. Recently, it was reported that most mRNAs of mouse forebrain are oscillating exclusively in synapse likely by mRNA transport from cytosol to synapse, and the mRNA localization and the local translation are related to sleep/wake cycle [35, 36].
Molecular mechanisms of circadian clock development during ontogenesis In vitro differentiated mouse ES and iPS cells require an approximately 14-day culture time for circadian clock development, and the discernible and robust circadian oscillation does not emerge immediately after the loss of pluripotency [26, 30, 37, 38]. It is suggested that additional mechanisms are necessary for the development of the circadian clock after cell differentiation. Our previous work [20, 26, 30, 37-39] has proposed a two-step mechanism as a working hypothesis for circadian clock development during ontogeny [30]. The first step is the cell-lineage determination process from an undifferentiated to a differentiated state. The second step is a CLOCK protein rate-limiting TTFL network maturation process. CLOCK protein expression is suppressed posttranscriptionally in the first step, and this posttranscriptional suppression gradually subsides during the second step [30]. The gradual upregulation in the expression of CLOCK proteins is concomitant with the increase in the amplitude of circadian molecular oscillation. NPAS2, a paralogue of CLOCK that can compensate for CLOCK function [40, 41], is hardly expressed in undifferentiated mouse cells [30]; therefore, posttranscriptional suppression of CLOCK proteins is one of the key mechanisms of the development of the circadian clock. We have previously reported
5
that Dicer/Dgcr8-dependent miRNAs-mediated repression and Clock mRNA export retardation are the main mechanisms of CLOCK posttranscriptional suppression. These suppressive mechanisms may be gradually canceled during the second step of the circadian clock development [30]. This stepwise differentiation process may be required for the development of circadian molecular oscillation [30, 37]. Perturbations of the differentiation process by genetic modifications, such as DNA methyltransferase (Dnmt1, Dnmt3a, and Dnmt3b) knockouts, c-Myc overexpression, or Kpna2 overexpression, prevent the development of the circadian molecular oscillation. The perturbation of the normal differentiation process in the first step may inhibit cells from starting the developmental upregulation of CLOCK protein expression in the second step [30, 37]. Interestingly, mouse multipotent germline stem (mGS) cells [42], a type of pluripotent stem cells, also present posttranscriptional suppression of CLOCK protein expression and circadian molecular oscillation development similarly to ES cells and iPS cells during in vitro differentiation (Figure 2) [30]. Furthermore, we recently suggested that posttranscriptional suppression of CLOCK proteins also occurs in human early-stage development by analysis using human iPS cells [39]. Human iPS cells require longer differentiation times in culture for the development of the circadian molecular oscillations [39]. This may be related to the difference in the gestation periods between mouse and human. The circadian oscillation suppression in the first step cannot be rescued by CLOCK overexpression [30], suggesting that other mechanisms are involved. Although further elucidation is needed to understand the molecular mechanisms, the core clock proteins and genes may be in different states between normal rhythmic cells with circadian clock and non-rhythmic cells. The state of most core clock molecules in non-rhythmic cells seems to have inhibitory effects on the cellular circadian oscillation. Although Per2 gene expression, like Npas2, is tightly suppressed in mouse ES cells, most core clock genes are transcribed at similar expression levels in the rhythmic differentiated cells. As described above, the CLOCK posttranscriptional suppression
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and the low-level Npas2 expression suggest that E-box-driven gene expressions such as Nr1d1 and Dbp [43] are inhibited in the cells, like Bmal1 knockout mice [44]. However, these clock genes are expressed at almost similar levels between ES cells and the rhythmic differentiated cells. This discrepancy may arise from the different epigenetic state of overall genome between ES cells and the differentiated cells or E-box-binding transcriptional factors such as MYC, which is highly expressed in ES cells. On the other hand, it was reported about the effect of dominant-negative BMAL1 (BMAL-DN) overexpression in ES cells [26]. BMAL1-DN has the lack of the C-terminus and strongly suppresses the BMAL1/CLOCK-mediated transcription [45]. Although in NIH3T3 cells with the circadian molecular oscillation, the BMAL1-DN overexpression indicated the suppression of the clock gene sets including Dbp, the BMAL1-DN suppressive effect in ES cells is not observed in the clock gene set. This result support the CLOCK posttranscriptional suppression in ES cells. The other components of clock also seem to be regulated for the suppression of clock molecular oscillation not at the level of transcription but at the level of translation and/or the protein modification. PER1 proteins in mouse pluripotent stem cells such as ES cells, iPS cells, and mGS cells, are exclusively localized to the cytoplasm (Figure 2) [37]. In normal rhythmic differentiated cells, PERs and CRYs can shuttle dynamically between the nucleus and cytoplasm independently, but they are mainly localized to the nucleus. Some modifications, such as phosphorylation and ubiquitination, of these negative regulators modulate the subcellular dynamics and protein stability [46-52]. PER2 is phosphorylated by CK2 and GSK3beta, and these modifications change its subcellular localization [50, 53]. In addition, PER-CRY binding induces the accumulation of the complex in the nucleus and stabilizes PER proteins [54-56]. In future, it will be necessary to elucidate whether these molecular mechanisms that occur in rhythmic cells also function in non-rhythmic cells, such as ES cells.
CLOCK suppression in human epigenetic cancers Interestingly, we found that posttranscriptional suppression of CLOCK
7
proteins is also observed in some types of human epigenetic cancers, such as Wilms tumor and malignant rhabdoid tumor [57]. This suggests not only the disruption of the circadian clock in cancer but also that epigenetic cancers might undergo deviation from the normal
cellular differentiation
process.
Conversely,
it
could reflect the
pathophysiological significance of CLOCK protein suppression. Although the relationships between cancer and circadian clock disruption have been reported in several studies [58-67], the viewpoint of cellular differentiation coupled to the circadian clock may be useful to further investigate in these settings.
Carrier proteins of the circadian clock proteins It is important to regulate the subcellular localization of circadian clock molecules in the 24-h oscillation period. Many types of carrier proteins have been identified as regulators of the subcellular localization of clock proteins. These carrier proteins recognize nuclear localization signals in the clock proteins and transport them from the cytoplasm to the nucleus. KPNB1, also known as importin subunit beta-1, is associated with KPNAs (importin subunit alpha) and translocates the carrier substrates from the cytoplasm to the nucleus. KPNB1 interacts mainly with PERs and mediates PER and CRY nuclear transport [68]. Other carrier proteins, TNPO1, facilitate the nuclear localization of PER1, but not PER2 [69]. More recently, it was reported that non-coding RNAs are also related to the localization of clock proteins [70]. One member of the Kpna family, Kpna2, has been identified as an importin alpha subunit, and its expression is abundant in undifferentiated cells, such as ES cells. KPNA2 are reported to regulate the differentiation state of cells by promoting OCT3/4 nuclear entry and preventing OCT6 nuclear entry, leading to cellular differentiation [71, 72]. Recently, we found that Kpna2 overexpression during in vitro differentiation of ES cells has inhibitory effects on the development of the circadian clock and the nuclear localization of PERs. However, the binding interaction between KPNA2 and PERs is considered to be very weak. Therefore, KPNA2 overexpression during in vitro differentiation of ES cells may inhibit the process of cellular differentiation and indirectly
8
affect the abnormal localization of PER proteins to the cytoplasm [37].
Biological significance of arresting the TTFLs Clock genes and proteins in non-rhythmic cells may be regulated for arresting TTFLs, suggesting that circadian oscillation is disadvantageous in the early developmental stages. Although the biological significance has not yet been elucidated in mammals, in the fruit fly, Drosophila melanogaster, Clock (Clk) overexpression induces developmental lethality [73], and Clk posttranscriptional regulation is essential for adequate development [74]. This suggests that regulation of CLOCK expression is essential not only for the circadian clock emergence but also for the developmental process as a whole. Interestingly, in mammals, circadian clock arrest may be not only due to defective TTFLs by different states of circadian clock molecules. Although it is believed that the maternal circadian rhythm entrains the fetus [15, 17, 18, 75], in our study, gene expression was not rhythmic in the mouse heart at E10–12, suggesting that maternal circadian clock entrainment in the embryo is prevented by unknown mechanisms in early development [30]. This suggests the presence of multi-layered mechanisms that suppress both the TTFLs of the circadian clock and the maternal clock-entrained gene cycles during early development and might highlight further the biological significance of the suppression of the circadian clock in early developmental stages.
Figure legends Figure
1.
Circadian
clock
development
is
tightly
coupled
to
cellular
differentiation. The core TTFLs of the circadian molecular oscillation in ES cells are not detectable, but the in vitro differentiation of ES cells induces a cell-autonomous robust circadian oscillation. The circadian oscillation disappears after reprogramming to iPS cells.
9
Figure 2. CLOCK protein expression is up-regulated and PER proteins translocate from the cytoplasm to the nucleus during in vitro differentiation, correlating with the emergence of the “24-h” oscillation. (A) Morphology of ES cells, mGS cells, and iPS cells. Scale bars = 100 µm. (B) The circadian oscillations are emerged gradually in the pluripotent stem cells during in vitro differentiation
[30].
Representative
bioluminescence
traces
in
undifferentiated
pluripotent stem cells carrying Bmal1-luc reporters (top panels) and averaged bioluminescence traces in vitro differentiated pluripotent stem cells at Day 7, 14, and 28. Data are shown with s.e.m. (n = 4-6). (C) The suppression of CLOCK protein expression and the cytoplasmic localization of PER are observed in the undifferentiated pluripotent stem cells [30, 32]. Immunofluorescence study of endogenous CLOCK and PER1 proteins in ES cells, mGS cells, iPS cells, and 28-day differentiated ES cells. Arrowheads indicate feeder cells. Scale bars = 25 µm. Part of data were adapted and modified from Umemura et al. [30].
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S0022-2836(20)30035-8
DOI:
https://doi.org/10.1016/j.jmb.2019.11.026
Reference:
YJMBI 66400
To appear in:
Journal of Molecular Biology
Received Date: 15 October 2019 Revised Date:
26 November 2019
Accepted Date: 26 November 2019
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Development of the Circadian Core Machinery in Mammals
Yasuhiro Umemura and Kazuhiro Yagita*
Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kyoto, 602-8566, Japan
*
Correspondence author: Kazuhiro Yagita ([email protected])
Phone: +81-75-251-5313 Fax: +81-75-241-1499
Declarations of interest: none
Highlights Mammalian cell-autonomous circadian clock development is coupled with cellular differentiation. The circadian clock emerges gradually during ontogeny. The core clock proteins and genes may be in different states between normal rhythmic cells with circadian clock and non-rhythmic cells. Posttranscriptional suppression of CLOCK proteins is one of the key mechanisms of the circadian clock development.
Keywords (5) Cellular differentiation, posttranscriptional regulation, CLOCK, circadian rhythm, cellular circadian clock
1
Abstract The emergence of circadian molecular oscillation is observed as a gradual process during the development in mammals. Pluripotent stem cell differentiation cultures recapitulate this process, whereas reprogramming into an undifferentiated state reverses it. These findings indicate that the circadian clock is tightly coupled to the state of cellular differentiation. The state of the circadian core machinery in non-rhythmic cells may be different from that in rhythmic cells. In this review, we describe the circadian rhythm development during ontogeny in mammals and focus on the molecular mechanisms that suppress circadian molecular oscillations during early development and in pluripotent stem cells. We also discuss the biological implications of repressing cellular circadian oscillation in non-rhythmic cells.
2
Introduction The mammalian circadian clock regulates diverse physiological functions in the whole body, such as the sleep–wake cycle, hormone release, body temperature, and metabolism. The central pacemaker of the circadian clock is the suprachiasmatic nucleus (SCN) in the hypothalamus. The SCN tunes the peripheral tissue clocks in anticipation of the cyclic environmental changes of the rotating earth. Each organ and also each cell, in addition to cultured cell lines, are endowed with an intrinsic cellular circadian clock [1-4]. The molecular principle of the cellular circadian clock is driven by transcriptional/translational feedback loops (TTFLs) composed of a subset of circadian clock genes. At the core of the TTFLs are two transcriptional factors, BMAL1 (also called ARNTL) and CLOCK. BMAL1 and CLOCK form a heterodimer that actively works in the induction of gene transcription by binding to E-box enhancer elements. Their induced gene expression includes their negative regulators Period (Per1, 2, 3) and Cryptochrome (Cry1, 2). The core circadian clock proteins assemble into a larger than 1-MDa macromolecular complex, which include PER and CRY in the nucleus and cytoplasm [5]. Once the BMAL1–CLOCK heterodimer forms a complex with PER and CRY proteins, it loses its transactivation activity. PERs and CRYs are reported to inhibit the inducible gene expression by promoting the dissociation of the BMAL1–CLOCK heterodimers from DNA [6]. In addition, BMAL1–CLOCK heterodimers also induce the expression of Rev-erbα (Nr1d1) and Rev-erbβ (Nr1d2), whose proteins repress Bmal1 expression by binding to the RORE promoter element [7, 8]. This process accrues the delay in gene expression of the clock components, and this delay in the TTFLs leads to circadian rhythmicity. Other proteins are involved in the regulation of this process and have been featured in this special issue and other reviews [9, 10].
Circadian development during ontogenesis Although almost all somatic cells are equipped with an intrinsic circadian clock, it has been reported that some cell types, including zygotes, the early embryo, and germline cells, do not have a robust circadian clock [11-13]. In recent decades, a
3
gradual circadian development during ontogeny has been reported [14-17]. In the mouse, embryonic tissues, such as the heart and liver, show circadian rhythms at around E13–18 [18-21]. Although the mouse SCN at E13.5 displays no circadian oscillations, the circadian rhythm of the SCN develops at E14.5 [22]. Human circadian rhythms also emerge gradually. The circadian rhythm of body temperature emerges immediately after birth in full-term infants [23], followed by the hormonal circadian rhythms between 3 and 6 months of age [23], with the sleep–wake cycle becoming more stable after 6 weeks of life [24]. Interestingly, in zebrafish, the circadian molecular oscillation is developed within one day of fertilization [25]. The different circadian clock formation periods may be attributed to species-specific developmental processes.
Circadian clock development tightly coupled with cellular differentiation state Recently, it has been reported that, despite mouse pluripotent stem cells such as embryonic stem (ES) cells having no discernible circadian molecular oscillations of TTFLs, in vitro differentiation of ES cells presents a circadian oscillation of clock gene expression cell-autonomously [26, 27]. Reprogramming of somatic cells using Yamanaka factors (Oct3/4, Klf4, Sox2, and c-Myc) [28] to produce induced pluripotent stem (iPS) cells results in the disappearance of the established circadian rhythm, suggesting that the circadian clock development is tightly coupled with the cellular differentiation state (Figure 1) [26]. During cell differentiation, genome-wide epigenetic modifications occur, and lineage-specific gene regulatory networks are established. Each undifferentiated cell is considered to follow a lineage-specific pathway to differentiate adequately as described in Waddington’s epigenetic landscape [29]. Almost all differentiated cells ultimately establish the TTFLs of the core circadian clock. The core circadian clock gene network regulates the diverse lineage- and tissue-specific gene expression as a circadian output. Consequently, higher-order physiological functions are acquired in the whole body. For example, the circadian clock in the mouse embryonic heart gradually develops from E10 after organogenesis, and a circadian molecular oscillation is observed from E17
4
[30]. In young adults, clock-controlled heart-specific genes are expressed [31]. It is also considered that other tissues acquire a core circadian molecular oscillation during ontogeny, at which point clock-controlled tissue-specific output genes are expressed. It is still unknown how tissue-specific gene expression becomes under the control of the core circadian clock after cell differentiation. The regulation may be related to the several circadian regulation of mRNA transcripts. Circadian regulations reside not only in the process of transcription but also mRNA translation and modification such as ploy-A modification, RNA methylation, and RNA-editing [32-34]. Recently, it was reported that most mRNAs of mouse forebrain are oscillating exclusively in synapse likely by mRNA transport from cytosol to synapse, and the mRNA localization and the local translation are related to sleep/wake cycle [35, 36].
Molecular mechanisms of circadian clock development during ontogenesis In vitro differentiated mouse ES and iPS cells require an approximately 14-day culture time for circadian clock development, and the discernible and robust circadian oscillation does not emerge immediately after the loss of pluripotency [26, 30, 37, 38]. It is suggested that additional mechanisms are necessary for the development of the circadian clock after cell differentiation. Our previous work [20, 26, 30, 37-39] has proposed a two-step mechanism as a working hypothesis for circadian clock development during ontogeny [30]. The first step is the cell-lineage determination process from an undifferentiated to a differentiated state. The second step is a CLOCK protein rate-limiting TTFL network maturation process. CLOCK protein expression is suppressed posttranscriptionally in the first step, and this posttranscriptional suppression gradually subsides during the second step [30]. The gradual upregulation in the expression of CLOCK proteins is concomitant with the increase in the amplitude of circadian molecular oscillation. NPAS2, a paralogue of CLOCK that can compensate for CLOCK function [40, 41], is hardly expressed in undifferentiated mouse cells [30]; therefore, posttranscriptional suppression of CLOCK proteins is one of the key mechanisms of the development of the circadian clock. We have previously reported
5
that Dicer/Dgcr8-dependent miRNAs-mediated repression and Clock mRNA export retardation are the main mechanisms of CLOCK posttranscriptional suppression. These suppressive mechanisms may be gradually canceled during the second step of the circadian clock development [30]. This stepwise differentiation process may be required for the development of circadian molecular oscillation [30, 37]. Perturbations of the differentiation process by genetic modifications, such as DNA methyltransferase (Dnmt1, Dnmt3a, and Dnmt3b) knockouts, c-Myc overexpression, or Kpna2 overexpression, prevent the development of the circadian molecular oscillation. The perturbation of the normal differentiation process in the first step may inhibit cells from starting the developmental upregulation of CLOCK protein expression in the second step [30, 37]. Interestingly, mouse multipotent germline stem (mGS) cells [42], a type of pluripotent stem cells, also present posttranscriptional suppression of CLOCK protein expression and circadian molecular oscillation development similarly to ES cells and iPS cells during in vitro differentiation (Figure 2) [30]. Furthermore, we recently suggested that posttranscriptional suppression of CLOCK proteins also occurs in human early-stage development by analysis using human iPS cells [39]. Human iPS cells require longer differentiation times in culture for the development of the circadian molecular oscillations [39]. This may be related to the difference in the gestation periods between mouse and human. The circadian oscillation suppression in the first step cannot be rescued by CLOCK overexpression [30], suggesting that other mechanisms are involved. Although further elucidation is needed to understand the molecular mechanisms, the core clock proteins and genes may be in different states between normal rhythmic cells with circadian clock and non-rhythmic cells. The state of most core clock molecules in non-rhythmic cells seems to have inhibitory effects on the cellular circadian oscillation. Although Per2 gene expression, like Npas2, is tightly suppressed in mouse ES cells, most core clock genes are transcribed at similar expression levels in the rhythmic differentiated cells. As described above, the CLOCK posttranscriptional suppression
6
and the low-level Npas2 expression suggest that E-box-driven gene expressions such as Nr1d1 and Dbp [43] are inhibited in the cells, like Bmal1 knockout mice [44]. However, these clock genes are expressed at almost similar levels between ES cells and the rhythmic differentiated cells. This discrepancy may arise from the different epigenetic state of overall genome between ES cells and the differentiated cells or E-box-binding transcriptional factors such as MYC, which is highly expressed in ES cells. On the other hand, it was reported about the effect of dominant-negative BMAL1 (BMAL-DN) overexpression in ES cells [26]. BMAL1-DN has the lack of the C-terminus and strongly suppresses the BMAL1/CLOCK-mediated transcription [45]. Although in NIH3T3 cells with the circadian molecular oscillation, the BMAL1-DN overexpression indicated the suppression of the clock gene sets including Dbp, the BMAL1-DN suppressive effect in ES cells is not observed in the clock gene set. This result support the CLOCK posttranscriptional suppression in ES cells. The other components of clock also seem to be regulated for the suppression of clock molecular oscillation not at the level of transcription but at the level of translation and/or the protein modification. PER1 proteins in mouse pluripotent stem cells such as ES cells, iPS cells, and mGS cells, are exclusively localized to the cytoplasm (Figure 2) [37]. In normal rhythmic differentiated cells, PERs and CRYs can shuttle dynamically between the nucleus and cytoplasm independently, but they are mainly localized to the nucleus. Some modifications, such as phosphorylation and ubiquitination, of these negative regulators modulate the subcellular dynamics and protein stability [46-52]. PER2 is phosphorylated by CK2 and GSK3beta, and these modifications change its subcellular localization [50, 53]. In addition, PER-CRY binding induces the accumulation of the complex in the nucleus and stabilizes PER proteins [54-56]. In future, it will be necessary to elucidate whether these molecular mechanisms that occur in rhythmic cells also function in non-rhythmic cells, such as ES cells.
CLOCK suppression in human epigenetic cancers Interestingly, we found that posttranscriptional suppression of CLOCK
7
proteins is also observed in some types of human epigenetic cancers, such as Wilms tumor and malignant rhabdoid tumor [57]. This suggests not only the disruption of the circadian clock in cancer but also that epigenetic cancers might undergo deviation from the normal
cellular differentiation
process.
Conversely,
it
could reflect the
pathophysiological significance of CLOCK protein suppression. Although the relationships between cancer and circadian clock disruption have been reported in several studies [58-67], the viewpoint of cellular differentiation coupled to the circadian clock may be useful to further investigate in these settings.
Carrier proteins of the circadian clock proteins It is important to regulate the subcellular localization of circadian clock molecules in the 24-h oscillation period. Many types of carrier proteins have been identified as regulators of the subcellular localization of clock proteins. These carrier proteins recognize nuclear localization signals in the clock proteins and transport them from the cytoplasm to the nucleus. KPNB1, also known as importin subunit beta-1, is associated with KPNAs (importin subunit alpha) and translocates the carrier substrates from the cytoplasm to the nucleus. KPNB1 interacts mainly with PERs and mediates PER and CRY nuclear transport [68]. Other carrier proteins, TNPO1, facilitate the nuclear localization of PER1, but not PER2 [69]. More recently, it was reported that non-coding RNAs are also related to the localization of clock proteins [70]. One member of the Kpna family, Kpna2, has been identified as an importin alpha subunit, and its expression is abundant in undifferentiated cells, such as ES cells. KPNA2 are reported to regulate the differentiation state of cells by promoting OCT3/4 nuclear entry and preventing OCT6 nuclear entry, leading to cellular differentiation [71, 72]. Recently, we found that Kpna2 overexpression during in vitro differentiation of ES cells has inhibitory effects on the development of the circadian clock and the nuclear localization of PERs. However, the binding interaction between KPNA2 and PERs is considered to be very weak. Therefore, KPNA2 overexpression during in vitro differentiation of ES cells may inhibit the process of cellular differentiation and indirectly
8
affect the abnormal localization of PER proteins to the cytoplasm [37].
Biological significance of arresting the TTFLs Clock genes and proteins in non-rhythmic cells may be regulated for arresting TTFLs, suggesting that circadian oscillation is disadvantageous in the early developmental stages. Although the biological significance has not yet been elucidated in mammals, in the fruit fly, Drosophila melanogaster, Clock (Clk) overexpression induces developmental lethality [73], and Clk posttranscriptional regulation is essential for adequate development [74]. This suggests that regulation of CLOCK expression is essential not only for the circadian clock emergence but also for the developmental process as a whole. Interestingly, in mammals, circadian clock arrest may be not only due to defective TTFLs by different states of circadian clock molecules. Although it is believed that the maternal circadian rhythm entrains the fetus [15, 17, 18, 75], in our study, gene expression was not rhythmic in the mouse heart at E10–12, suggesting that maternal circadian clock entrainment in the embryo is prevented by unknown mechanisms in early development [30]. This suggests the presence of multi-layered mechanisms that suppress both the TTFLs of the circadian clock and the maternal clock-entrained gene cycles during early development and might highlight further the biological significance of the suppression of the circadian clock in early developmental stages.
Figure legends Figure
1.
Circadian
clock
development
is
tightly
coupled
to
cellular
differentiation. The core TTFLs of the circadian molecular oscillation in ES cells are not detectable, but the in vitro differentiation of ES cells induces a cell-autonomous robust circadian oscillation. The circadian oscillation disappears after reprogramming to iPS cells.
9
Figure 2. CLOCK protein expression is up-regulated and PER proteins translocate from the cytoplasm to the nucleus during in vitro differentiation, correlating with the emergence of the “24-h” oscillation. (A) Morphology of ES cells, mGS cells, and iPS cells. Scale bars = 100 µm. (B) The circadian oscillations are emerged gradually in the pluripotent stem cells during in vitro differentiation
[30].
Representative
bioluminescence
traces
in
undifferentiated
pluripotent stem cells carrying Bmal1-luc reporters (top panels) and averaged bioluminescence traces in vitro differentiated pluripotent stem cells at Day 7, 14, and 28. Data are shown with s.e.m. (n = 4-6). (C) The suppression of CLOCK protein expression and the cytoplasmic localization of PER are observed in the undifferentiated pluripotent stem cells [30, 32]. Immunofluorescence study of endogenous CLOCK and PER1 proteins in ES cells, mGS cells, iPS cells, and 28-day differentiated ES cells. Arrowheads indicate feeder cells. Scale bars = 25 µm. Part of data were adapted and modified from Umemura et al. [30].
10
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