Chen and Mas Genome Biology (2019) 20:62 https://doi.org/10.1186/s13059-019-1672-9 REVIEW Open Access Interactive roles of chromatin regulation and circadian clock function in plants Z. Jeffrey Chen1,2 and Paloma Mas3,4* Genome-wide analyses have provided evidence of the Abstract pervasive role of the clock controlling the rhythms of Circadian rhythms in transcription ultimately result in a large fraction of the transcriptome [6–11]. The rhythms oscillations of key biological processes. Understanding in gene expression are transduced into oscillations of pro- how transcriptional rhythms are generated in plants tein activities involved in a myriad of signaling pathways. provides an opportunity for fine-tuning growth, Germination, growth, development [12–15], and re- development, and responses to the environment. sponses to abiotic [16, 17] and biotic [18, 19] stresses are Here, we present a succinct description of the just a few of the many examples of processes controlled plant circadian clock, briefly reviewing a number of by the plant circadian clock. Recent studies have expanded recent studies but mostly emphasizing the components the range of the pathways controlled by the clock. Indeed, and mechanisms connecting chromatin remodeling the repertoire of circadianly regulated processes also in- with transcriptional regulation by the clock. The cludes the regulation of other oscillators such as the cell possibility that intergenomic interactions govern cycle. The study showed that circadian control of the cell hybrid vigor through epigenetic changes at clock loci cycle is exerted by setting the time of DNA replication li- and the function of epialleles controlling clock output censing [20]. Similarly, another recent study has shown traits during crop domestication are also discussed. that the circadian clock regulates age-dependent and dark-induced leaf senescence [21, 22]. The mechanisms rely on the clock-controlled regulation of the positive Introduction aging regulator ORESARA1 (ORE1) [21, 22] and on the re- The Earth’s rotation around its axis leads to changes in pression of miR164, a post-transcriptional repressor of light and temperature that have shaped life over evolu- ORE1 [21]. Leaf senescence also relies on the function of tion. It is therefore not surprising to find 24-h rhythms circadian clock components that gate the signaling of the in physiology, metabolism, and development that oscil- phytohormone jasmonate [23]. Overall, the circadian late in synch with the day and night cycles [1, 2]. A ro- clock ensures proper phasing of these biological processes bust and yet flexible cellular machinery, the circadian in consonance with the environment. The clock function clock, generates the rhythms by integrating the environ- thus requires precise information on the environmental mental cues and the temporal information into 24-h bio- fluctuations. This occurs through the activity of photore- logical oscillations [1, 2]. As sessile organisms, plants ceptors that perceive and transduce light and temperature must effectively perceive and appropriately respond to changes. Hence, the clock machinery exploits photorecep- the changes in environmental conditions for proper tor function for time-of-day information [24]. Resetting of growth and survival [3, 4]. Consistently, it has become the clock by these environmental changes is assumed to increasingly clear that the circadian clock controls the occur through changes in the expression and activity of phase of a vast collection of pathways in plants. essential clock components [25]. A highly precise circadian clock function is crucial for proper plant adaptation to the environment [5]. Components and regulatory mechanisms of circadian clock activity in Arabidopsis * Correspondence: paloma.mas@cragenomica.es The main Arabidopsis clock components entangle in a 3 Center for Research in Agricultural Genomics (CRAG), Consortium complex regulatory network that generates rhythms in CSIC-IRTA-UAB-UB, Campus UAB, Bellaterra, 08193 Barcelona, Spain expression and activity exerted at specific phases during 4 Consejo Superior de Investigaciones Científicas, 08028 Barcelona, Spain Full list of author information is available at the end of the article the day and night [26]. Briefly, the morning-expressed © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Chen and Mas Genome Biology (2019) 20:62 Page 2 of 12 and partially redundant single MYB transcription factors were able to regulate gene expression [51] in a tissue-spe- known as CCA1 (CIRCADIAN CLOCK ASSOCIATED1) cific manner [52, 53]. Despite the organ-specific [27] and LHY (LATE ELONGATED HYPOCOTYL) [28] synchronization [54], long-distance signals are important repress the expression of the evening-expressed clock for clock synchronization in distal parts of the plant [55, genes during the day [26]. In turn, evening-expressed 56]. Short-distance communication or circadian coupling clock components such as TOC1/PRR1 (TIMING OF also plays a role in synchronization. The degree of coup- CAB2 EXPRESSION1/PSEUDO RESPONSE REGULA- ling varies depending on tissues and conditions. For in- TOR1) [29, 30] repress the morning genes during the stance, cells at the vasculature present stronger coupling night [31–33]. TOC1 belongs to a family of clock repres- than leaf cells [57, 58], which show only weak coupling sors (including PRR9, PRR7, PRR5, and PRR3 in addition [59–61]. In root cells, a continuous resetting of the circa- to TOC1) that sequentially suppress CCA1 and LHY tran- dian oscillations results in a stripe wave originating at the scription during the day [34]. Repression starts with PRR9 root tip [62], which shows strong cell-to-cell coupling function at early midday and is subsequently followed by [63]. Gould et al. [63] proposed that the variability in PRR7 and PRR5 later in the day [34] and by TOC1 at dusk coupling and period differences among different root cells and early evening [31–33]. TOC1 represses not only can explain the waves of clock activity in roots. CCA1 and LHY expression but also nearly all of the oscil- Synchronization in roots can also occur by light piping lator components [35]. Other evening-expressed regula- from shoots [64]. The shoot apex represents a particular tors, including LUX (LUX ARRYTHMO), ELF3 (EARLY example of short- and long-distance circadian communi- FLOWERING3), and ELF4 (EARLY FLOWERING4), cation, as rhythms at the shoot apex are highly synchro- form a protein complex (evening complex) that acts as a nized due to strong circadian coupling, and this function repressor of the morning-expressed PRR clock genes [36– is important for proper rhythms in roots [56]. 40]. Repression of the PRR genes by evening complex per- mits the rising phase of LHY and CCA1, which reach their Chromatin remodeling and transcriptional peak expression at dawn. regulation In addition to this battery of clock repressors, direct ac- Transcriptional rhythms underlie the circadian clock func- tivation of circadian gene expression relies on the function tion at its basis. As transcriptional regulation is largely of the single MYB REVEILLE/LHY-CCA1-LIKE (RVE/ dependent on chromatin status, understanding changes in LCL) transcription factors, which share a high sequence chromatin conformation is essential to fully comprehend homology with CCA1 and LHY, particularly in the MYB rhythms in transcription. Chromatin can be modified at domain [41]. RVE8, RVE6, and RVE4 directly interact with levels of DNA sequence, histones, and high-order chro- the clock-related components known as LNKs (NIGHT matin structure and organization [65–67]. DNA methyla- LIGHT-INDUCIBLE AND CLOCK-REGULATED) to ac- tion affects growth and development of plants and tivate the expression of clock genes such as TOC1 and animals in response to environmental cues [68–71] and is PRR5 [42–47]. The mechanisms of regulation rely on essential for animal development [72]. Plants are more tol- changes in chromatin modifications [42] and recruitment erant to mutations in DNA methylation pathways [68, 70], of the basal transcriptional machinery to the circadian loci and methylation mutants have few phenotypes, although [48]. Additional key clock components and post-transcrip- abnormal genetic lesions can develop over several genera- tional and post-translational mechanisms of regulation en- tions of self-pollination [73]. Unlike in animals in which sure smooth shapes of the oscillatory waves, fine-tuning methylation occurs almost exclusively in the CG context the robustness and precision of the clock. Altogether, the [74], with a few exceptions in stem cells [75], methylation complex regulatory circadian network at the core of the in plants occurs in CG, CHG, and CHH (H = A, T or C) clock ensures that the morning and evening clock tran- contexts through distinct pathways [71]. In Arabidopsis, scripts precisely peak at their corresponding phases [26]. METHYLTRANSFERASE 1 (MET1) and CHROMO- It was recently proposed that the complexity of the plant METHYLASE 3 (CMT3) are responsible for the mainten- circadian network might provide strength against extreme ance of CG and CHG methylation, respectively [76–78]. environmental conditions [49]. CHH methylation is established de novo through two Long-standing questions in plant circadian biology pathways. One involves biogenesis of small interfering deal with how the circadian clocks are organized within RNAs (24-nt siRNAs) that require Nuclear RNA Polymer- the plant body and whether there are overarching signals ase IV (D) Subunit1 (NRPD1) [79, 80] and are targeted to that synchronize the clocks in separate parts of the corresponding genomic loci by ARGONAUTE (AGO) plant. Nearly all cells possess clocks exhibiting various family members (AGO4 and AGO6), which are methyl- degrees of synchronization. Early studies reported that ated via DOMAINS REARRANGED METHYLTRANS- different rhythmic oscillations could be controlled by FERASE2 (DRM2) [81, 82]. The other pathway requires separate oscillators [50] and that autonomous clocks CHROMOMETHYLASE 2 (CMT2) through interacting Chen and Mas Genome Biology (2019) 20:62 Page 3 of 12 with DECREASE IN DNA METHYLATION1 (DDM1) in upregulated genes are associated with elevated acetylation histone H1-containing heterochromatic regions [83]. In levels in a locus-specific manner [102]. HDA6, a homolog addition to its establishment and maintenance, DNA of HDA19, affects CG and CHG methylation and is in- methylation can be actively removed by a family of bifunc- volved in silencing of TEs and uniparental rRNA genes tional methyl-cytosine glycosylases-apurinic/apyrimidinic subjected to nucleolar dominance [91]. Yeast Sir2 is an lyases through a base excision repair pathway [71]. These NAD-dependent histone deacetylase and plays a role in demethylases consist of REPRESSOR OF SILENCING 1 transcriptional silencing and delayed aging [103]. Mem- (ROS1) [84], DEMETER (DME) [85, 86], and DEMETER- bers of the SIRT family are associated with host–pathogen LIKE 2 and 3 (DML2 and DML3) [87, 88]. DNA methyla- interactions in Arabidopsis [104], and DNA fragmentation tion may change gene expression, inducing imprinting and cell death in rice through changes in H3K9ac [105]. and activation of transposable elements (TEs) and Like histone acetylation, histone methylation is revers- TE-associated genes, in response to developmental and ible; but unlike histone acetylation, histone methylation environmental cues [71]. can be associated with gene activation or repression de- In addition to DNA methylation, the accessibility of pending on the site of modifications [90]. In general, his- chromatin is dynamically regulated by a suite of histone tone H3 lysine 4 (H3K4) and H3K36 methylation is modifications, dubbed “histone code” [66]. Core histones related to gene expression, while H3K9 and H3K27 (H2A, H2B, H3, and H4) can be covalently modified at methylation is related to gene repression and hetero- different positions of amino-terminal tails by different chromatin formation [65]. Histone methyltransferases modifications, including acetylation, methylation, ubiqui- (HMTs), as writers, are a group of proteins that contain tination, phosphorylation, glycosylation, carbonylation, SET (SU(VAR)/E(Z)TRX) domains to methylate histone ADP ribosylation, sumoylation, and biotinylation [66, 89, H3 lysine residues. Plant SET domain proteins can be 90]. These modifications, alone or in combination, can divided into four groups based on Drosophila members change the accessibility of chromatin structures in the E(Z), TRX, AHS1, and SU(VAR)3-9 [106]. Some SET do- vicinity of genes to transcription machinery, leading to main proteins belong to the members of Polycomb transcriptional activities and epigenetic phenomena [91]. group (PcG) and regulate imprinting and gene expres- Histone acetylation and deacetylation are reversible and sion during plant and animal development [107], while controlled by histone acetyltransferases (HATs) as others are related to transcriptional activation and silen- “writer” and histone deacetylases (HDACs) as “eraser” cing [90, 91]. HMTs can have specificity for methylating [89, 91, 92]. Most acetylation marks such as histone 3 ly- lysine residues of histone H3. For example, SUVH4 (aka sine 9 acetylation (H3K9ac), histone 3 lysine 14 acetyl- KRYPTONITE) is related to histone 3 lysine 9 mono/ ation (H3K14ac), and histone 3 lysine 36 acetylation dimethylation (H3K9me1/2), Arabidopsis TRITHORX5 (H3K36ac) are associated with gene activation [89]. and 6 (ATX5 and ATX6) are associated with H3K27 Plants have multiple gene families of HATs and HDACs methylation, and ASH 1 Homolog2 (ASHH2) mediates [89, 93]. Plant HATs are grouped into two based on H3K36me2/3 methylation. SET Domain Group2 (SDG2) localization (nuclei or cytoplasm) [89] or five depending on is a major writer for H3K4me1/2/3 and regulates plant sequence features [93]. The major class of HATs is the ho- growth and development [108], while ATX1 (SDG27) mologs of the GCN5 family in yeast and Tetrahymena [94]. and ATX2 (SDG30) display locus-specific H3K42/3 Mutation of an Arabidopsis AtGCN5 results in the reduc- methylation [109]. tion of histone H3 or H4 acetylation in the light-responsive Histone demethylases or eraser proteins belong to two promoter regions and reduced expression of the groups with distinct biochemical properties. Lysine-spe- light-inducible genes [95]. Moreover, AtGCN5 interacts cific demethylase1 (LSD1) acts through amine oxidation, with CBF1 and mediates cold-inducible gene expression while a large family of Jumonji C (JmjC) [96], which is regulated by the circadian clock [97]. domain-containing proteins directly reverse histone Plants have homologs of histone deacetylases, including methylation by an oxidative demethylation process RPD3 (reduced potassium dependency protein3)-like and [110]. Arabidopsis has four LSD members and 21 JmjC sir2-like (silent information regulator protein 2), which homologs [111]; they play important roles in plant are conserved across all eukaryotes [89, 91]. In addition, growth and development. JMJ5 (ELF6) and JMJ12 (rela- plants have a specific histone deacetylase, HD2, which is tive early flowering6 (REF6)) promote early and late identified in maize [98] and involved in gene repression flowering phenotypes in their respective mutants [112]. and seed development in Arabidopsis [99]. RPD3-like Increase in Bonsai Methylation1 (IBM1) is a JmjC mem- HDACs, HDA19 or HD1, in Arabidopsis exhibit histone ber (JMJ25) which counteracts H3K9 methylation, in deacetylase activity [100] and are a general transcriptional addition to CHG DNA methylation, to prevent spread- regulator [101]. In the athd1 mutant, approximately 7% of ing of silencing from TEs and heterochromatin to active the genes are either up- or downregulated, while the genes [113]. Chen and Mas Genome Biology (2019) 20:62 Page 4 of 12 The interplay between histone acetylation, deacetylation, increased H3ac that likely favors an open chromatin methylation, and demethylation is dynamic and interactive. conformation, facilitating the accessibility of the tran- For example, AtGCN5 and AtHDA19 are required for scriptional machinery and, hence, the transcription of H3K36ac homeostasis. H3K36ac and histone 3 lysine 36 the gene. Later studies showed that, during the day, the trimethylation (H3K36me3) show negative crosstalk, which clock-related MYB transcription factor RVE8 contributes is mediated by GCN5 and the histone methyl transferase to the hyper-acetylated state of H3 at the TOC1 pro- SDG8 [114]. SUVH4 is a HMT for H3K9 methylation and moter, antagonizing CCA1’s repressive function. The interacts with CHROMOMETHYLASE 3 to maintain molecular mechanism by which RVE8 facilitates the in- CHG DNA methylation at silenced loci [115]. When H3K9 creased H3ac was later identified [48] (see below). At and H3K27 methylation levels are high, these sites are void the peak of TOC1 expression, histone deacetylase activ- of acetylation. Silenced rDNA loci are de-repressed by ities contribute to the removal of acetyl groups from H3, 5-aza-2′-deoxycytidine (aza-dC), a chemical inhibitor for leading to a hypo-acetylated state that correlates with DNA methylation, and trichostatin A, a chemical inhibitor the declining phase of TOC1 mRNA [125]. In addition, for histone deacetylation, suggesting interactive roles of CHE, another clock component, is repressed at ZT6 and DNA methylation and histone deacetylation in gene re- ZT9 in the AtHD1 mutant [126]. Further studies showed pression [116]. Moreover, other modifications of histones, that CHE interacts with AtHD1 to repress CCA1 expres- such as phosphorylation and ubiquitination, may also con- sion; CCA1 repression was relieved in the che athd1 tribute to cell cycle regulation and gene expression during double mutant. The interaction of clock–chromatin pro- plant development. Inhibition of histone deacetylation by teins would add another layer of complexity in the circa- trichostatin A in Nicotiana sylvestris protoplasts reduces dian transcriptional feedback loop. H3S10ph at anaphase and telophase and induces the accu- Other histone marks also associate with the chromatin mulation of metaphase cells [117]. state at the TOC1 promoter [127–129]. For instance, Chromatin modification can also occur at levels of nu- histone 3 lysine 4 trimethylation (H3K4me3) accumula- cleosome remodeling and replacement of core histone with tion is also rhythmic and peaks just after the peak of histone variants [91, 118]. DECREASE IN DNA METHY- H3ac. The rhythms were observed under different pho- LATION1 (DDM1), encoding a SWI2/SNF2-like chromatin toperiods and under constant light conditions, suggest- remodeling protein in plants, mediates DNA methylation ing a direct link with the circadian clock [127–129]. and genome stability [119]. In Arabidopsis, histone variant Accumulation of H3K4me3 antagonizes the binding of H2A.Z is antagonistic with DNA methylation [120] and me- clock repressors such as CCA1, thus preventing repres- diates thermosensory responses [121]; H2A.W marks the sion from occurring too early and ensuring a precise heterochromatin with H3K9 methylation [122]. Moreover, 24-h rhythmic expression [129]. The histone methyl- the three-dimensional structure in nuclei can also impact transferase SDG2/ATXR3 (SET DOMAIN GROUP 2/ chromatin dynamics and spatial-temporal transcriptional ARABIDOPSIS TRITHORAX RELATED 3) was pro- regulation in animals [123] and possibly in plants. posed to contribute to the H3K4me3 accumulation as Dynamic regulation of DNA methylation and chroma- clock gene expression, H3K4me3 marks, and clock re- tin modifications have been recognized to be essential pressor binding were affected in plants miss-expressing for transcriptional regulation in response to growth and SDG2/ATXR3 [129]. The oscillatory accumulation of development in plants and animals [124]. The chromatin these histone marks paralleling the rhythmic mRNA ac- landscape is interwoven with circadian control of tran- cumulation is not exclusive for TOC1 but is also present scriptional regulatory networks with the corresponding at the promoters of other oscillator genes such as CCA1, spatial and temporal information [123]. LHY, PRR9, PRR7, and LUX [129]. It was proposed that these histone marks could provide the rhythmic activa- The interplay between chromatin remodeling and tion necessary for expression, particularly in a circadian the Arabidopsis circadian clock signaling network full of repressors [130] (Fig. 1). A The first report describing a connection between chro- recent report has further explored the connection be- matin remodeling and the Arabidopsis circadian clock tween the clock and chromatin dynamics identifying a uncovered a remarkable parallelism between the rhyth- H3K9ac/H3K27ac/H3S28ph signature as a mechanism mic changes in mRNA and the oscillatory pattern of his- controlling diurnal transcript changes [131]. Baerenfaller tone 3 acetylation (histone 3 lysine 9 and 14 acetylation, et al. [131] proposed that H3K4me3 marks and the ab- H3K9/14ac) at the promoter of the clock gene TOC1 sence of the repressive H3K9me2 and histone 3 lysine [125]. The study also showed that repression of TOC1 at 27 trimethylation (H3K27me3) might be responsible for dawn coincided with the binding of CCA1 to the TOC1 the control of the steady active states. promoter and with a hypo-acetylated state of H3. During Another chromatin-activating function relies on HUB1 the day, the TOC1 mRNA rising phase correlates with (HISTONE MONOUBIQUITINATION1), an unusual Chen and Mas Genome Biology (2019) 20:62 Page 5 of 12 Ac Ac Ac Ac Ac HDAC HUB1 HUB1 HAF2 MLK Me3 Me3 Ub Ub Ub Ac AcPh Ph Me3 Me3 Me3 Ph Me3 Ub Ac Me3 Ph Me3 Ph RVE8 SDG2 LDL PRR9 PRR9 JMJ JMJ LDL CCA1 HDA6 TPL LDL CCA1 HDA6 TPL Me2 Me2 Me2 Me2 Me2 Me2 TPL Clock output traits Fig. 1 Main transcription factors (rectangles) and chromatin-related components (ovals) shaping the circadian waveform of clock gene expression. The rhythms in gene expression are transduced into oscillations of gene and protein activities involved in a myriad of clock output traits. The main factors regulating TOC1 expression are shown: activators (green), repressors (red), and chromatin-related factors with a yet-to-be fully defined molecular function within the clock (purple). Components described to be involved in the regulation of other clock genes are also included (ovals with dotted lines). Further details are given in the text. Adapted from [125] ubiquitin E3 ligase that is involved in histone H2B ubi- gene promoters [48]. This mechanism exemplifies an ef- quitination (H2Bub) [132]. Studies with hub1-1 mutant fective way for controlling chromatin status, transcript plants showed a reduced amplitude in the expression of initiation and elongation, and proper rhythms in nascent clock genes as well as in histone H2Bub and H3K4me3 RNAs [48]. These findings are consistent with a recent marks associated with the gene coding regions [133]. study showing that the expression of a subset of clock These results together with the fact that H2Bub facili- genes is downregulated in elo mutant plants [136]. These tates the function of the FACT (facilitates chromatin mutants are deficient in the elongator complex, which transcription) complex in humans [134] suggest a role promotes RNA polymerase II-mediated transcript elong- for HUB1 on transcriptional elongation in plants [135]. ation through epigenetic activities such as histone acetyl- It is noteworthy that the direct connection of the circa- ation [136] (Fig. 2). dian clock with the FACT complex was previously Not just activating histone modifications are associated hinted at [125] and later mechanistically confirmed [48]. with the clock as other histone marks such as histone 3 Indeed, rhythms in transcript initiation and elongation lysine 36 dimethylation (H3K36me2) appear to nega- of evening-expressed clock genes rely on the rhythmic tively correlate with the expression of the oscillator recruitment of RNA polymerase II and the FACT com- genes [128]. Furthermore, the transcriptional repression plex to their promoters. The mechanism depends on the of CCA1 and LHY is regulated by members of the Grou- interaction of the clock-related components LNKs with cho/Tup1 protein family, topless/topless-related (TPL/ RNA polymerase II and the FACT complex. In turn, the TPR), which interact with the PRR protein family at the interaction of LNKs with RVE8, which is able to bind to CCA1 and LHY promoters [137]. This repression is alle- the target promoters, allows the recruitment of the tran- viated following treatment with the histone deacetylase scriptional machinery and associated chromatin remod- inhibitor trichostatin A, suggesting that the histone dea- eling complexes to rhythmically co-occupy the clock cetylase activity is required for TPL function. Also, Chen and Mas Genome Biology (2019) 20:62 Page 6 of 12 Elongator P LNKs SP S T RNA Pol P P SY II FACT RVE8 Clock gene Me3 Me3 Ac AcPh Ph Me3 Me3 Ub Ub Ub Me3 Ph Me3 Ac Me3 Ph Me3 Ub Ph Nascent RNAs SDG2 HAF2 MLK SDG2 HUB1 Fig. 2 Protein complex formation, including clock proteins and the transcriptional machinery, controls the rhythms of chromatin modifications and nascent RNA of clock genes. Rhythmic binding of RVE8 (REVEILLE8) to the target clock promoters and its interactor LNKs (NIGHT LIGHT- INDUCIBLE AND CLOCK-REGULATE) facilitates the rhythmic recruitment of the transcriptional machinery, and the FACT (facilitates chromatin transcription) complex. This complex interplay facilitates oscillations in chromatin modifications and the rhythms of clock nascent RNAs. Further details are given in the text. Adapted from [48] PRR9, TPL, and HDA6 (histone deacetylase 6) form a the question of the JMJD5/JMJ30 mechanism of action protein complex likely involved in H3 deacetylation within the clock. Notably, a short-period phenotype was [137]. Therefore, TPL functions as an important also found in jmjd5 mutant mammalian cells, and both chromatin-related repressor of core oscillator genes. orthologs were able to lengthen circadian period when The clock seems in turn to feedback on chromatin expressed in the reciprocal system [142]. These results regulation as the expression of a number of chromatin suggest a similar function of JMJD5/JMJ30 in plants and remodeling factors rhythmically oscillates [138]. Tran- mammals. scriptional regulation by the clock might be a way to The clock component CCA1 has also been associated temporally control the expression of the oscillator genes with other chromatin-related factors. For instance, or other clock input or output genes. For instance, MUT9P-like-kinase 4 (MLK4), a kinase that phosphory- CCA1 directly binds to the promoter of PKL (PICKLE) lates histone H2A at S95, directly interacts with CCA1 [139]. The gene encodes an ATP-dependent chromatin and this interaction permits MLK4 to bind to the pro- remodeling factor that negatively regulates photo- moter of the clock- and flowering-related gene GIGAN- morphogenesis. Zha et al. [139] show that CCA1 regula- TEA (GI) [143]. CCA1 also interacts with a subunit of tion of PKL could be important for hypocotyl elongation the Swi2/Snf2-related ATPase (SWR1) and NuA4 com- under warm temperatures. It is interesting to note that plexes [143]. These complexes participate in the depos- the expression of PKL is downregulated in cca1 mutant ition of the histone variant H2A.Z and histone H4 plants [139], which suggests that CCA1 activates PKL acetylase activities, respectively. Mutation of MLK4 transcription. This activating function is in clear contrast results in decreased GI expression, which correlates with with the CCA1 repressive role of core clock genes. reduced histone 2A serine 95 phosphorylation CCA1 also regulates the expression of HAF2 (HISTONE (H2AS95Ph), H2A.Z, and histone 4 acetylation (H4Ac) ACETYLTRANSFERASE OF THE TAFII250 FAMILY 2). at the GI locus. The regulation seems to be important HAF2 seems to promote H3ac at the PRR5 and LUX for flowering as mlk4 mutant plants flower late [143]. promoters to activate their expression [140]. Notably, ELF3 also co-immunoprecipitates with MLK1– Two reports also showed a connection of JMJD5/JMJ30, 4 [144] and analyses of mlk1–4 loss-of-function mutants a putative histone demethylase Jumonji C (JmjC) protein, showed an alteration of circadian period [144]. It would with the plant circadian clock [141, 142]. JMJD5/JMJ30 be interesting to fully uncover the relevance of MLK1–4 has a peak of expression in the evening, a pattern of ex- interaction with ELF3. CCA1 and LHY also interact with pression that is regulated by direct binding of CCA1 and the LSD1-like histone demethylases LDL1 and LDL2 to LHY to the JMJD5/JMJ30 promoter to repress its expres- repress TOC1 and likely other CCA1 gene targets [145]. sion [141]. JMJD5/JMJ30 in turn promotes CCA1 and LDL1 and LDL2 also interact with the histone deacety- LHY expression and consequently jmjd5/jmj30 mutant lase HDA6 so that they coordinately control histone de- plants display a short-period circadian phenotype [141, methylation and deacetylation at the TOC1 locus [145]. 142]. However, overexpression of JMJD5/JMJ30 also leads Thus, HDA6 not only interacts with PRR9 and TPL but to short-period circadian phenotypes [141], which raises also with CCA1 and LHY. Yeast two-hybrid assays have Chen and Mas Genome Biology (2019) 20:62 Page 7 of 12 shown that CCA1 also interacts with the deacetylase through epigenetic mechanisms to save the energy from SIRT1 (SIRTUIN1) [138]. These results are interesting defense to promote growth [97]. Under stress condi- as mammalian SIRT1 interacts with the core clock com- tions, however, expression of stress-responsive genes ponent CLOCK to regulate its chromatin-related func- from both parents is inducible at certain times and in tion [146]. However, further experiments are necessary certain stress environments, depending on the type of to fully confirm the CCA1–SIRT1 interaction in plants biotic or abiotic stress, for defense, which could have and to demonstrate the biological relevance of such an minimized the energy cost, compared with constitutive interaction. expression of stress-responsive genes in their parents, of defense for growth [97]. When the stress-responsive genes Chromatin and clock interplay in cannot be epigenetically suppressed in the hybrids, they suf- Arabidopsis hybrids and other crops fer from hybrid vigor to cause hybrid weakness [158]. Circadian regulation is highly conserved among flowering Moreover, the circadian clock regulates expression of many plants, and the function of central clock genes in Arabi- other genes involved in biosynthesis and signaling of phyto- dopsis can be complemented by homologous genes in rice hormones, including auxin and ethylene [159, 160]. Diurnal and maize [147, 148]. Changes in plant growth and devel- downregulation of ethylene biosynthesis genes in hybrid opment in response to adaptation and selection could plants could also lead to growth vigor; however, the regula- have an epigenetic basis [149]. Natural variation of circa- tion of ethylene biosynthetic genes by CCA1 is indirect dian clock features contributes to plant fitness over a wide [161], suggesting involvement of other factors such as geological spectrum [150], although the genetic and/or epigenetic ones and other clock components. epigenetic basis for altered clock parameters is unclear. In There is evidence that expression of circadian clock addition to their sessile nature, plants have plasticity in genes is affected by DNA methylation through the their genomes that can be reprogrammed through RdDM pathway [162]. In the RdDM gene mutants ago4 hybridization and polyploidy, providing a pervasive force and nrpd1, CHH methylation levels in the CCA1 pro- in the evolution of eukaryotic genomes [151, 152]. In Ara- moter region are reduced, while the CCA1 expression bidopsis suecica, a naturally formed allotetraploid and its waveform is increased. This change in DNA methylation resynthesized siblings, expression waveforms (or ampli- is associated with the parent-of-origin effect on CCA1 tudes) of circadian clock genes (e.g., CCA1, LHY, TOC1, expression in the hybrids, as if CCA1 expression is and GI) are altered because of histone acetylation and imprinted by the RdDM pathway, which is consistent methylation changes presumably resulting from interge- with maternal expression of NRPD1 in Arabidopsis nomic interactions between the hybridizing parents [153]. [163]. However, we do not know how DNA methylation As a result, the circadian-mediated output regulatory controls CCA1 expression or overall circadian rhythms. pathways, including photosynthesis and starch metabol- CCA1 expression is not altered in the maintenance ism, stress responses, and phytohormonal production, are methylation mutant met1 or ddm1 [162]. Methylome rewired in response to the clock change [154]. The more analysis in 3-h time intervals does not seem to support starch is produced during the day [153], the more can be an overall diurnal rhythm of DNA methylation in A. degraded and utilized at night [155] to promote plant thaliana (unpublished data). growth. However, it is unclear whether epigenetic modifi- Cotton fiber development is influenced by seasonal cation of circadian clock genes is a result of interspecific changes, probably because of temporal regulation in dif- hybridization or the cause of the altered circadian regula- ferent growth conditions during the winter and summer tory networks. It is also notable that expression waveforms [164]. This change is coincident with CHH methylation (or amplitudes) of the circadian clock genes are changed, changes in the promoters of some fiber-related genes, while the diurnal or circadian period is maintained in which is confirmed by reducing ROS1 expression in the these examples to sustain growth vigor. transgenic cotton, promoting fiber growth in the sum- In an ever-changing environment, plant growth is also mer. The role of DNA methylation in seasonal variation influenced by other factors including defense to biotic hints at a connection with the circadian clock, but it is and abiotic stresses. This trade-off balance is mediated unclear if the methylation variation affects expression of through the internal circadian clock that regulates ex- circadian clock genes in cotton. pression of biotic and abiotic stress-responsive genes Flowering time in plants is controlled by the photo- [156]. Under normal growth conditions, parents have a period pathway that involves CONSTANS (CO) and flow- memory to elevate expression of stress-response genes, ering locus T (FT), which are regulated by the circadian which is inherited from their adaptation to local envi- clock and light signaling pathways [165]. In Arabidopsis, ronments [97, 157]. This stress-response memory is overexpressing CCA1 delays flowering [27], while the cca1 erased and reprogrammed in Arabidopsis thaliana hy- mutant has an early flowering phenotype [166]. In sor- brids by expression changes in the circadian clock genes ghum, pseudoresponse regulator 37 (PRR37) activates CO Chen and Mas Genome Biology (2019) 20:62 Page 8 of 12 and represses FT in the long-day condition, causing late chromatin modifications. However, it remains to be de- flowering, and consequently, the mutant prr37 has an fined whether circadian clock components recruit the early flowering phenotype [167]. Similarly, PRR and GI epigenetic factors to genomic targets for circadian out- homologs are associated with flowering time quantitative put or the epigenetic modifications facilitate the recruit- trait loci in rice, maize, and other crops (reviewed in ment of clock and other factors for circadian regulation. [168]). Although epigenetic regulation of vernalization Answering this question is not trivial but it will provide and flowering time has been extensively investigated key information about how the epigenetic and circadian [169], little is known about the epigenetic link with circa- transcriptional landscapes are temporally coordinated. In dian regulation in control of flowering time. A recent addition, spatial coordination of circadian and chromatin study demonstrated that some key regulators controlling regulation is important to plant growth and develop- photoperiodic flowering, such as CO or CO-Like (COL) ment. Research is rapidly and significantly advancing our genes, are among the epialleles that are generated during understanding of how the clock works in different cells allotetraploid cotton evolution [170]. GhCOL2 is methyl- and tissues and within the whole plant. The cell and tis- ated and silenced in the wild relatives and hypo-methyl- sue specificity of the circadian transcriptional landscapes ated and expressed in the cultivated cotton. Reducing might very well be correlated with similar spatial speci- COL2 expression in the cultivated cotton delays flowering. ficities of chromatin remodeling. It is possible that spe- The result suggests a role for epialleles in the cific chromatin components and marks connected with circadian-mediated pathway that regulates flowering time clock loci only function at particular cells or tissues de- and shapes crop domestication. pending on the specificities of clock outputs on those cells and tissues. Future directions Another interesting aspect that remains to be fully ex- The studies summarized in this review clearly establish plored is the evolutionary trajectory of clock and chro- that the plant circadian clock is directly connected with matin remodeling. From the initial studies in the model chromatin modifications. Despite the wealth of informa- system A. thaliana, research is increasingly advancing in tion on the interactive interplay between chromatin analyses of clock and chromatin function in other components and circadian regulators, we are still far non-model plants. The use of multidisciplinary ap- from a complete understanding of the molecular and proaches, including chronobiology, chromatin biology, cellular basis underlying this connection. Many ques- mathematical modeling, and molecular evolution, will tions remain to be answered. For instance, how do envir- help us to define the similarities and differences across onmental cues trigger the clock–chromatin interactions, the plant kingdom over evolution. These studies will also spontaneously or in a sequential manner? The diurnal provide information on how the circadian clock function fluctuations in light and temperature correlate well with is able to regulate the physiological and developmental oscillatory patterns of histone modifications at clock loci. diversity of different plants such as monocots and eudi- However, it is not fully known whether the clock cots. Lastly, the development of new tools and integra- gates specific chromatin signatures in response to fluctu- tive methods, including but not limited to chromatin ating environmental stresses. Similarly, does the and transcriptomics profiles at the single-cell level, will stress-dependent transcriptional activation or repression further uncover the intrinsic complexity of chromatin of clock genes depend on gated chromatin changes? Is it and circadian regulatory networks at both cellular and possible that the gated chromatin signatures provide a organismal levels. memory of recent transcriptional activity? Addressing these questions is pertinent in the context of climate Abbreviations CCA1: CIRCADIAN CLOCK ASSOCIATED1; ELF: EARLY FLOWERING; change and global warming, which impose a real threat FACT: Facilitates chromatin transcription; H2Bub: Histone 2B ubiquitination; to agricultural productivity. Based on the role of the cir- H3K27ac: Histone 3 lysine 27 acetylation; H3K36ac: Histone 3 lysine 36 cadian clock in plant responses to stresses, a full under- acetylation; H3K36me2: Histone 3 lysine 36 dimethylation; H3K4me3: Histone 3 lysine 4 trimethylation; H3K9ac: Histone 3 lysine 9 acetylation; standing of the environmental factors coordinating the H3S28ph: Histone 3 serine 28 phosphorylation; HAT: Histone chromatin and transcriptional landscapes would be crit- acetyltransferase; HDAC: Histone deacetylase; HMT: Histone ical to improve plant fitness and productivity. methyltransferase; LDL: LSD1-like histone demethylase; LHY: LATE ELONGATED HYPOCOTYL; LNK: NIGHT LIGHT-INDUCIBLE AND CLOCK- The intricate connection between the circadian oscilla- REGULATED; LSD: Lysine-specific demethylase; MLK: MUT9P-LIKE-KINASE; tions and chromatin modifications also opens a key un- PRR: PSEUDO RESPONSE REGULATOR; RVE: REVEILLE; SDG: SET domain group; resolved question about which one is the “cause” and SIRT1: Sirtuin1; TE: Transposable element; TOC1: TIMING OF CAB2 EXPRESSION1 which one is the “consequence”. It is known that circa- dian clock components and chromatin regulators form Acknowledgements functional protein complexes that correlate with changes We would like to apologize to colleagues whose work has not been included in circadian gene expression, DNA methylation, and in this review due to space constraints. Chen and Mas Genome Biology (2019) 20:62 Page 9 of 12 Funding 17. Legnaioli T, Cuevas J, Mas P. TOC1 functions as a molecular switch connecting ZJC’s laboratory is funded by the National Institutes of Health (GM109076) the circadian clock with plant responses to drought. EMBO J. 2009;28:3745–57. and National Science Foundation (IOS1739092). PM’s laboratory is funded by 18. Zhou M, Wang W, Karapetyan S, Mwimba M, Marqués J, Buchler NE, and the Spanish Ministry of Economy and Competitiveness (BFU2016-77236-P) Dong, X. Redox rhythm reinforces the circadian clock to gate immune from the European Regional Development Fund and by the Generalitat de response. Nature. 2015;523:472–476. Catalunya (AGAUR; 2017 SGR 1211). We also acknowledge the CERCA 19. Li Z, Bonaldi K, Uribe F, Pruneda-Paz JL. A localized Pseudomonas syringae Programme/Generalitat de Catalunya and the financial support from the infection triggers systemic clock responses in Arabidopsis. Curr Biol. 2018;28: Spanish Ministry of Economy and Competitiveness, through the “Severo Ochoa 630–9 e634. Programme for Centres of Excellence in R&D” 2016–2019 (SEV-2015-0533). 20. Fung-Uceda J, Lee K, Seo PJ, Polyn S, De Veylder L, Mas P. The circadian clock sets the time of DNA replication licensing to regulate growth in Authors’ contributions Arabidopsis. Dev Cell. 2018;45:101–13 e104. Both authors wrote the manuscript and approved the final version. 21. Kim H, Kim HJ, Vu QT, Jung S, McClung CR, Hong S, et al. Circadian control of ORE1 by PRR9 positively regulates leaf senescence in Arabidopsis. Proc Competing interests Natl Acad Sci U S A. 2018;115:8448–53. 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