Biosci. Biotechnol. Biochem., 77 (1), 10–16, 2013 Award Review From a -Based Mechanism to an External Coincidence Model Responsible for Photoperiod and Temperature Control of Plant Architecture in Arabodopsis thaliana

Takafumi YAMASHINO

Laboratory of Molecular and Functional Genomics, School of Agriculture, Nagoya University, Chikusa-ku, Nagoya 464-8601, Japan

Online Publication, January 7, 2013 [doi:10.1271/bbb.120765]

Circadian clocks enable organisms to define subjec- in many biological processes of almost all eukaryotic tive time, that is, to anticipate diurnal day and night organisms including plants.1) A clock provides plants cycles. Endogenous circadian rhythms regulate many with an adaptive advantage to anticipate and respond to aspects of an organism’s physiological and morpholog- daily changes in environmental conditions such as day ical growth and development. These daily oscillations and night, and seasonal changes in photoperiod.2,3) are synchronized to the environment by external cues Endogenous circadian rhythms were first studied by such as light and temperature, resulting in enhanced observation of daily leaf movements in plants. An fitness and growth vigor in plants. Recent findings insightful experimental approach to monitor biolumi- concerning biochemical properties of central oscillators nescence of transgenic plants harboring clock or clock- in thaliana have advanced our understand- controlled gene fusions to the firefly luciferase ing of circadian clock function. Central oscillators are gene (LUC), developed by Millar and Kay, made it composed of three classes of transcriptional . possible to characterize biological rhythms more pre- The interactions among them include a repressilator cisely in a nondestructive manner.4) In a model higher structure. Output from the circadian clock is trans- plant A. thaliana, genetics, reverse genetics and bio- duced through regulating of downstream chemical study uncovered various types of clock- genes directly by the oscillator components. The essen- associated genes in concert with progress in the tial role of the output pathway in the circadian system is monitoring technique of clock functions.5–8) Based on to make different elementary steps responsible for daily current knowledge of the molecular functions of clock- cellular processes exert maximum effects at specific associated genes,9) supported by modeling and simula- times of the day. Recently, significant progress was tion,10) central oscillator components to define the made in defining the mechanisms by which plant growth molecular mechanism of circadian clock are classified on a day-to-day basis is activated at specific times of the into three classes of transcriptional regulators: Myb- day in a manner dependent on photoperiod and temper- related proteins, CCA1 and LHY,11,12) pseudo-response ature conditions. Plant growth is controlled by the clock regulators with the CCT motif (PRR family), PRR9, through interactions with light and phytohormone PRR7, PRR5 and TOC1,13) and a recently identified signaling. This review focuses on the node that connects evening complex (EC) composed of LUX/PCL1 (GARP clock output to light and phytohormone signaling that family protein), ELF3 and ELF414) (Fig. 1). Transcripts coordinates plant growth with rhythmic changes in the of these clock genes are regulated in a circadian fasion. environment. CCA1 and LHY are expressed with sharp peaks in the morning.11) Circadian wave of sequential PRR9, PRR7 Key words: ; circadian clock; and PRR5 transcripts is observed during the day.13) The external coincidence; light signaling; EC genes (LUX, ELF3 and ELF4) and TOC1 are phytohormone signaling expressed from evening to midnight.15–18) Importantly, mutational lesions in the genes encoding these clock oscillators affect the robustness of circadian rhythms I. Transcriptional Regulation-Dependent severely. A cca1 lhy double mutant exhibits dampened Circadian Clock Mechanism in A. thaliana with a short period.19) A prr9 prr7 prr5 triple mutant shows an arrhythmic circadian pheno- Circadian clocks are intrinsic, entrainable mecha- type.20,21) Loss of function mutants of any one of the nisms that generate biological rhythms with approx- genes encoding EC also result in arrhythmia.15–18) imately a 24-h period. Circadian rhythms are widespread These results suggest that each class of clock compo-

This review was written in response to the author’s receipt of the Japan Society for Bioscience, Biotechnology, and Agrochemistry Award for the Encouragement of Young Scientists in 2009. Correspondence: Fax: +81-52-789-4091; E-mail: [email protected] Abbreviations: BR, brassinosteroid; ChIP-Seq, chromatin immunoprecipitation followed by deep sequencing; DELLAs, DELLA proteins; EC, evening complex; GA, gibberellic acid; R/FR, red/far-red Circadian Clock-Dependent Diurnal Control of Plant Architecture 11

Day and LHY indirectly through the direct inhibition of

PRR9 PRRs, which are direct repressors of CCA1 and LHY. PRR7 TOC1 affects every class of oscillator components PRR5 directly as a transcriptional (Fig. 1). In good agreement with this model, a mutant exhibits a short period and overexpression of TOC1 results in an TOC1 33,34) CCA1 LUX arrhythmic phenotype. The real biological clock ELF4 ELF3 LHY system of A. thaliana is more complicated than the Morning Evening to night simplified structure focused around the repressilator. In fact, it is suggested that direct and/or indirect transcrip- Fig. 1. A Model for Simplified Transcriptional Repression-Based tional activation function of the above-mentioned Interactions among Central Oscillators in A. thaliana. central oscillators (CCA1,35) LUX,15) ELF3,17) and ELF418,36)) and other oscillators (NOX,37) LWD1,38) nents plays a phase-specific essential role in oscillator and RVE839,40)) are incorporated into this clock network. functions, determining topological vulnerability of the Autoregulation of CCA1/LHY,11,12) the PRR family,29) clock network. Clarification of the biochemical activity and the EC genes30,36) is also suggested to be involved in of these clock components has advanced our under- the clock mechanism. Furthermore, the whole structure standing of clock mechanism. CCA1 and LHY directly the plant clock includes post-translational modification repress the expression of TOC1, LUX and ELF4 by of the oscillator components such as CK2 mediated binding specifically to a cis-element within their phosphorelation of CCA1 and LHY,25) phosphorelation promoters known as the evening element (EE: AAAAT- and ZTL mediated degradation of PRRs,41–43) and ATCT), a motif that is overrepresented in the promoters regulation of the EC by COP1 and GI,44) which is of clock-regulated evening expressed genes.15,22–25) It probably responsible for cellular localization, activity, was recently unraveled that PRR9, PRR7, and PRR5 act and/or stability of the proteins. Despite the complexity as transcriptional repressors in the clock network. They of the circadian clock mechanism, the direct transcrip- associate with CCA1 and LHY promoters in vivo and tional repression-based interactions among the central repress these genes from early daytime until the middle oscillators (CCA1/LHY, PRRs, and EC) to establish of the night.26) The molecular properties of TOC1 have the repressilator structure shown in Fig. 1 might be also been characterized, demonstrating it is a DNA- important for the Arabidopsis clock to generate robust binding transcriptional repressor of CCA1 and (self-sustaining) and entrainable biological rhythms in LHY.10,27,28) In addition to CCA1 and LHY, TOC1 binds response to external time cues such as light and to the promoters and inhibits the expression of almost all temperature. the above-mentioned central oscillator components, PRR9, PRR7, PRR5, LUX, and ELF4.27,28) Combinato- II. External Coincidence Mechanism to rial analysis of genome-wide expression study and Regulate Plant Architecture under Day chromatin immunoprecipitation followed by deep se- and Night Cycle Conditions in A. thaliana quencing (ChIP-Seq) lead to identification of direct target genes for PRR529) and TOC1.27,28) The DNA It is generally admitted that growth is controlled binding motifs enriched in these PRR family protein through interactions between light and phytohormone share weak sequence similarity, making it difficult to signaling.45,46) Photoreceptor mutants and mutants of identify the consensus sequence.27–29) This suggests that phytohormone biosynthesis or signaling exhibit abnor- the PRR family functions as transcriptional repressors in malities in photomorphogenesis processes during de- combination with other transcription factors to define the etiolation including elongation response of the embry- sequence specificity for promoter binding. In EC onic stem, the hypocotyl.47) Elongation of hypocotyls is proteins, LUX is responsible for the DNA binding also observed in shade avoidance responses under low activity for target genes. Protein binding microarray red/far-red (R/FR) ratios and/or low blue light inten- (PBM) experiments identified the consensus LUX bind- sity conditions.47) Involvement of phytohormones as ing site (LBS: GAT[A/T]CG).30) LBS is present at the well as photoreceptor mediated light signaling is promoters of PRR9, PRR7, TOC1, LUX, and ELF4.10,30) evident also in the control of growth under a canopy.48) Recent studies indicate that LUX functions as a tran- On the other hand, it was reported from a long time ago scriptional repressor of PRR9, TOC1, and its own that circadian dysfunction causes aberrant hypocotyl promoter,10,30) and that ELF3 and ELF4 function as elongation patterns.49) In fact, almost all the central transcriptional repressors of PRR9 and PRR7.31) Taken oscillator mutants of Arabidopsis show longer or shorter together, it was proposed that the clock gene circuit in A. hypocotyls than wild-type.9,50) Circadian clocks enable thaliana includes a repressilator structure (Fig. 1).10,32) organisms to define subjective time, that is, to anticipate The morning CCA1 and LHY can induce daytime diurnal day and night cycles. The essential role of the PRR9, PRR7, and PRR5 indirectly through the direct output pathway in the circadian system is to make inhibitory effect on the EC genes, which are direct different elementary steps (events) responsible for daily repressors of PRRs. Expression of daytime PRR9, PRR7 cellular processes exert maximum effect at the specific and PRR5 can lead to enhanced expression of the EC times of the day. It was a long mystery how the above genes indirectly from evening to midnight through the three independent mechanisms (light signaling, phyto- direct repression of CCA1 and LHY, which function as hormone signaling, and circadian clock) to serve plant direct repressors of the EC genes. Finally, activation of growth interact among themselves. The finding that the EC can feed back to the enhancement of morning CCA1 growth of hypocotyls in reaches maximum 12 T. YAMASHINO

APB domain Circadian rhythm Name AGI code (PIL motif) of transcripts

HFR1HFR1 At1g02340 A A

56 PIL1PIL1 At2g46970 P A PIL2/PIF6PIL2/PIF6 At3g62090 P A

59 PIF1/PIL5PIF1/PIL5 At2g20180 P A

69 PIF3PIF3 At1g09530 P A PIF4PIF4 At2g43010 P P (robust) 61 99 PIF5/PIL6PIF5/PIL6 At3g59060 P P (robust)

SPTSPT At4g36930 A A

68 ALTALC At5g67110 A A 57 PIF7PIF7 At5g61270 P P (robust)

78 PIF8PIF8 At4g00050 P P (moderate) (A: absent, P: present) 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0.00

APB domain bHLH domain

APB core HFR1 PIL1 PIL1 PIL2 PIL2 PIF1 PIF1 PIF3 PIF3 PIF4 PIF4 PIF5 PIF5 PIF7 PIF7 PIF8 PIF8 SPT ALC

Fig. 2. PIF Family of A. thaliana.

rates at dawn under short-day conditions, using infrared Photoperiod and Temperature Control of Plant Growth light imaging technique done by Nozue and collea- 51) gues, advanced our understanding about this is- DELLA Photoperiod ATHB2 sue.3,52–54) Compared with de-etiolation and shade (Light) Clock avoidance responses, growth is regulated on a daily PIF4/5 basis. It is well known that Arabidopsis growth under Temperature BR6OX2 long-day conditions results in short hypocotyls, and phyB HTX15 BIM1 Brassinosteroid short-day; long hypocotyls. The critical photoperiod to cause hypocotyl elongation of Arabidopsis green seed- Shade-Induced Growth Respnses lings is duration of around 12 h dark.55) It is demon- cry1 BR BZR1 strated that -interacting bHLH transcrip- Low blue DELLA Shade tion factor, PIF4 and PIF5 (Fig. 2) is predominantly PIF4/5 Photoperiod Clock involved in the photoperiodic control of hypocotyl Temeprature avoidance 51,55) Low R/FR growth. A pif4 pif5 double mutant almost or phyB PIF7 completely abolishes the photoperiodic response of hypocotyl elongation.51,55) PIF4 and PIF5 belong to the 56,57) Fig. 3. A Regulatory Pathway Guiding Elongation Growth Responses PIF family of eleven members (Fig. 2). The on a Day-to-Day Basis or on a Shade Avoidance Condition. primary sequences of the PIF family have characteristic domain structures. They contain the considerably con- served bHLH domains that are responsible for dimeri- PIF4,63) PIF5,63–65) and PIF7.66) In the context of zation and DNA binding to target genes (Fig. 2). N- relationship between circadian clock and light signaling, Terminal regions containing about 100 amino acids PIF4, PIF5, and PIF7 are distinguishing, because each designated the active phytochrome-binding (APB) do- of their transcripts shows a robust circadian rhythm with main (also called the PIL motif), which is necessary and a peak in the middle of the day, indicating they are sufficient for phyB interaction,58) is conserved among under the control of the circadian clock (Fig. 2).67,68) It eight members of the PIF family. Sequence alignments was reported recently that EC directly represses the showed that they share in common a significantly transcription of PIF4 and PIF5.14) While PIF4 is conserved APB core motif (Fig. 2). It is demonstrated expressed both in daytime and nighttime on short-days, that the interaction with photo-activated phyB induces it is expressed exclusively in the daytime under long- rapid phosphorelation, which leads to the 26S protea- day conditions (Fig. 4A).55) However, PIF4 is thought some-mediated degradation of PIF1,59–61) PIF3,62) to be inactivated during daytime by post-translational Circadian Clock-Dependent Diurnal Control of Plant Architecture 13

LD SD germination and chlorophyll biosynthesis as well as A 70–72) PIF4 mRNA PIF4 mRNA hypocotyl elongation. It was reported recently that, PIF4 activity PIF4 activity PIF4 targets PIF4 targets although PIF3 is not regulated in a circadian fashion, basal expression of PIF3 is also involved in the photoperiodic control of plant growth together with phys Clock Short phys PIF4 and PIF5.73) The functional broadness of PIF3 DELLAs photoperiod might be important in the PIF family to understand phytochrome-mediated signaling. In the context of ° ° relationship between circadian clock and phytohor- B 22 C 28 C PIF4 mRNA PIF4 mRNA mones signaling, gibberellic acid (GA) and brassinoste- PIF4 activity PIF4 activity roid (BR) are particularly important for the photo- PIF4 targets PIF4 targets periodic control of plant growth. It is shown that GA signaling is gated by the circadian clock through phys phys Clock DELLAs High DELLAs transcriptional regulation of the GA receptors, resulting temperature in higher stability of the DELLA proteins (DELLAs) during daytime and higher sensitivity at night,74) because GA perceived by the receptors leads to C SD LD degradation of DELLAs.75) In addition, blue light CO mRNA CO mRNA CO activity CO activity causes a considerable reduction in internal active GA FT mRNA FT mRNA in seedlings through induction of GA2ox transcripts (GA2ox1 and GA2ox2) and rapid reduction of GA20ox FKF1 transcripts (GA20ox1).65,76) These two mechanisms of Clock Long COP1 COP1 photoperiod phyB the regulation act on the cellular contents of the DELLAs synergistically under day and night cycle conditions, consistently with the earlier observation that the accumulation of DELLAs is more stimulated in D Circadian long-days than in short-days.77) Importantly, it is clock output demonstrated that DELLAs interact with PIF3 and PIF4 to inhibit the transcriptional activity of them.78,79) Diurnal Reductions in endogenous GA levels, through the plant application of a GA biosynthesis inhibitor or a mutant growth of GA biosynthesis (ga1), results in complete inhibition Light Phytohormones 77) signaling of hypocotyl elongation. Thus GA is prerequisite for signaling photoperiodic control of plant growth. Considering these facts, the gated GA signaling may also be involved in the Fig. 4. Schematic Representation of External Coincidence Models. mechanism to activate PIF4 transcriptional activity at External coincidence models to explain photoperiod (A) and temperature (B) controls of plant growth, and photoperiodic control the end of night specifically under short-day conditions of flowering (C). Diurnal elongation growth responses under natural independently of phyB (Figs. 3 and 4A). phyB and day- and night-cycle conditions in plants are accomplished by the DELLAs might therefore play the essentially same role interactions between circadian clock and light signaling, and in the photoperiodic control of plant growth. In the case between circadian clock and phytohormone signaling (D). of BR signaling, BR biosynthetic genes are diurnally regulated in such a way that BR accumulates in the regulations described above. Through these phyB- and middle of the light phase.80) BR perceived by the receptor clock-dependent mechanisms, it was speculated that leads to activation of BZR1 family transcription fac- PIF4 is activated at the end of night only under short- tors.81) It was found recently that activated BZR1 and day conditions to induce elongation of hypocotyls, PIF4 interact with each other to regulate common target because it is only when transcription of PIF4 coincides genes.82,83) It was also reported that relationship between with PIF4 protein stabilization that the transcriptional GA and BR signaling is important for positive regulation activity is activated.51,53,55) Inspection of genome-wide of growth.84) Under low blue light conditions transcriptome database combined with ChIP analysis such as shade, GA and BR levels might increase even in led to identification of ATHB2 as one of the direct the daytime. The involvement of PIF4 and PIF5 in shade targets of PIF4 and PIF5.69) Considering the expression avoidance responses under low blue light conditions is profiles of the ATHB2 gene under various photoperiod evident because the responses are significantly impaired conditions, it is suggested that PIF4 is actually activated in a pif4 pif5 double mutant.85) Taken together, it might at the end of night specifically under short-day be possible that BZR1-PIF4/5 complex is activated in conditions (Fig. 4A).69) The coordinate interplay be- the daytime under low blue light conditions (Fig. 3). In tween photoreceptor phyB and circadian clock makes it relevant to the shade avoidance responses, physiological possible for seedlings to grow in such a way that function of PIF7 was characterized recently. It was found elongation of hypocotyls is accelerated at the end of that PIF7 is predominantly required in shade avoidance night specifically in short-days due to coincidence responses under low R/FR conditions,66) though PIF4 between circadian clock-dependent internal and photo- and PIF5 are also involved in it (Fig. 3).63) Another period-dependent external time cues (Fig. 3). PIF3 is a interesting aspect with respect to relationship between foundation member of the bHLH family and is involved the circadian clock and phytohormone signaling is that in many aspects of phyB signaling including seed expressions of a set of phytohormone biosynthesis or 14 T. YAMASHINO signaling-associated genes correlate with time of hypo- III. Concluding Remarks and Future Per- cotyl growth, that is, they are diurnally induced at the end spectives of night in short-days.86) It is possible that PIF4 and PIF5 participate in this time of day- and photoperiod-specific Circadian clock, light signaling, and phytohormone gene expression. In fact, a genome-wide approach by signaling can be studied independently. Progress in each ChIP-Seq analysis identified about 1,000 PIF5 binding research consequently led to better understanding of sites on the chromosome under shade conditions, and plant growth on a day and night cycle basis. Some of the auxin biosynthesis or signaling-associated genes are de-etiolation mechanisms under the control of light and significantly detected as target genes of PIF5.87) These phytohormone signaling might be evolutionally co- are consistent with the earlier finding that transcriptional opted in the photoperiod and temperature controls of responses to auxin are gated by the circadian clock with diurnal plant growth. Since plants are sessile, adaptation the maximum sensitivity just before dawn.88) Although it to daily changes in environmental conditions brings is poorly understood how auxin is linked to the clock great advantages to them. Also, since light and temper- based plant growth, it is evident that auxin is involved in ature vary on time-to-time, season-to-season, and place- the elongation responses to serve plant growth.89–91) to-place bases, the plant circadian clock plays a pivotal It was confirmed recently that not only auxin-associated role in it. The external coincidence mechanism respon- genes (GH3.5, IAA19, IAA29), but also genes associated sible for photoperiod and temperature controls of plant with other growth-regulating hormones such as BR growth is established by the interactions between (BR6ox2), GA (GAI), ethylene (ACS8), and cytokinin circadian clock and light signaling, and between (CKX5) are induced in a time-of-day- and photoperiod- circadian clock and phytohormones signaling (Fig. 4D). specific manner in accordance with the PIF4 and PIF5 In this model, two external cues (i.e., photoperiod and dependent external coincidence model, suggesting that temperature) modify the phase of the rhythmic expres- the circadian clock orchestrates a variety of hormone- sion of PIF4 independently, but are integrated into the signaling pathways to regulate the photoperiod-depend- same circadian clock, light and phytohormone signaling- ent morphogenesis.92) As described above, the time-of- regulated PIF4 (and/or PIF5) output pathway, and this day- and photoperiod-specific plant growth is best in turn coordinately regulates a hormone-signaling explained by stimulation of the PIF4 transcriptional network to fit plant architectures appropriately to natural activity at the end of night specifically in short-days, domestic habitats. A long photoperiod inhibits elonga- due to the coincidence between the internal (circadian tion of hypocotyls and petiols, and a short photoperiod rhythm) and external (photoperiod) time cues, but enhances it. On the other hand, high temperature flexibility of the external coincidence model was enhances plant growth, and a low temperature inhibits challenged by the recent finding that elongation of it. Long photoperiods coincide with high temperatures, hypocotyls was markedly promoted at a high growth and short photoperiods with low temperatures in the temperature (i.e.,28C) in a PIF4-dependent man- natural environment. The plant circadian clock might ner.93,94) It was found that the PIF4 and PIF5-mediated buffer exaggerated responses throughout the whole plant external coincidence model is applicable to temperature life cycles by integrating both the photoperiod and control of diurnal plant growth, based on the observa- temperature signals into the external coincidence mech- tion that transcription of PIF4 occurs precociously at anism to serve diurnal plant growth, because plant the end of night under high temperature conditions even architecture is critically important in long distance in long-days (Fig. 4B).95) In accord with this, target transport for cell-to-cell communications (e.g., sink- genes of PIF4 were also induced at the end of night source relationship and signal transduction) to organize under these conditions, verifying the model (Fig. 4B).95) multi-cellular systems. However, it is poorly understood PIF4 regulates auxin biosynthesis at high tempera- how photoperiod and/or high temperature affect the ture.96,97) In addition to auxin, other phytohormones clock function per se that is responsible for the phase network is induced at high temperature as in short- control of rhythmic expression of PIF4. Functional days.95) The extended external coincidence mechanism modification of the activity of EC might be involved in explains how two environmental cues (i.e., photoperiod the sensitivity of PIF4 expression phase to photoperiods, and temperature), both of which vary on daily and because it represses the transcription of PIF4 and PIF5 season-to-season bases, are integrated into the same directly.14) Marvelously fascinating evidence was pre- clock and PIF4-mediated output pathway that regulate a sented recently with regard to the thermosensory hormone-signaling network to fit plant architectures mechanism in A. thaliana.103) The nucleosome struc- properly to domestic habitats. The circadian clock can tures of some temperature sensitive genes (e.g., HSP70) control multiple output pathways, depending on when are modified by the incorporation of histone H2A.Z in the clock opens the gate to the output pathways. The place of H2A as ambient temperature decreases.104) external coincidence mechanism of photoperiodic con- H2A.Z occupancy defines the state of transcriptional trol of plant growth is similar to that of the photo- activity of the genes. This finding might also help in periodic control of flowering time, in which the CO understanding how circadian rhythms are modified in transcription factor serves as the critical integrator for output pathways by temperatures. At the protein level, both clock and light signals.98,99) In the former case, the furthermore, the activities of PIF4 and PIF5 are thought clock opens the gate to PIF4/5 activity during extended- to be regulated intricately. In addition to DELLAs and night (end of night)inshort-days. In the latter case, the BZR1, PIF family protein HFR1 and HLH protein PAR1 clock opens the gate to CO activity during extended- interact with PIF4 and prevent it from binding to the daytime (end of day)inlong-days.100–102) These mech- target DNA.105,106) Stability of PIF4 is down-regulated anisms are mirror images of each other (Fig. 4C). by low temperature.107) It is known that PIF family Circadian Clock-Dependent Diurnal Control of Plant Architecture 15 protein SPT is involved in the control of plant growth 26) Nakamichi N, Kiba T, Henriques R, Mizuno T, Chua NH, and under low temperature conditions.108) Regulation of Sakakibara H, Plant Cell, 22, 594–605 (2010). biochemical activity of PIF family should also promote 27) Gendron JM, Pruneda-Paz JL, Doherty CJ, Gross AM, Kang SE, and Kay SA, Proc. Natl. Acad. Sci. 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