circadian posttranscriptional regulatory mechanisms in mammals

Circadian Posttranscriptional RegulatoryMechanisms in Mammals

Carla B. Green

Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111

Correspondence: [email protected]

The circadian clock drives rhythms in the levels of thousands of proteins in the mammaliancell, arising in part from rhythmic transcriptional regulation of the genes that encode them.However, recent evidence has shown that posttranscriptional processes also play a majorrole in generating the rhythmic protein makeup and ultimately the rhythmic physiology ofthe cell. Regulation of steps throughout the life of the messenger RNA (mRNA), rangingfrom initial mRNA processing and export from the nucleus to extensive control of translationand degradation in the cytosol have been shown to be important for producing the finalrhythms in protein levels critical for proper circadian rhythmicity. These findings will bereviewed here.

In mammals, cell-autonomous circadian clockscontrol rhythmic expression of thousands of

messenger RNAs (mRNAs), ultimately generat-ing daily rhythms in biochemistry, physiology,and behavior (Pittendrigh 1981a,b; Akhtar et al.2002; Panda et al. 2002; Storch et al. 2002; Uedaet al. 2002; Duffield 2003; Welsh et al. 2004;Reddy et al. 2006). This dynamic control ofgene expression is a hallmark of the mammaliancircadian clock, which is comprised of inter-locking transcriptional–translational feedbackloops (Lowrey and Takahashi 2004; Takahashiet al. 2008). Steady-state levels of �5%–10% ofthe mRNAs in any given tissue are rhythmic(Duffield 2003; Rey et al. 2011; Koike et al.2012; Menet et al. 2012). Many of these genesare regulated transcriptionally, either by directrhythmic transactivation by CLOCK/BMAL1,the central transcriptional activators of the

core clock mechanism, or indirectly by otherrhythmic transcription factors that are down-stream from the core loop. However, many stepsoccur between transcriptional initiation and ul-timate protein function and many, if not all, ofthese steps could conceivably be subject to cir-cadian regulation.

Transcripts are capped and spliced whilethey are still being transcribed and then the 30

ends are cleaved and polyadenylated. Each ofthese steps requires many accessory proteinsand/or small RNAs and frequently many alter-nate splice forms and alternate polyadenylationsites can be chosen. RNAs are coated with RNA-binding proteins, forming ribonucleoproteincomplexes and are exported to the cytoplasm(and in some cases to specific regions of thecell), where they are translated and eventuallydegraded. During the time in the cytoplasm, the

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mRNAs may be deadenylated and stored in atranslationally silent form, followed by laterreadenylation to make them translationallycompetent. Regulation of the protein productsthat result from translating these mRNAs de-pends on extensive regulation at many or all ofthese steps.

Much of the work on the mechanisms ofcircadian gene expression has focused on tran-scriptional control and the primary readoutshave been steady-state mRNA levels, as a resultlargely of the ease of making these measure-ments. However, extensive evidence is accumu-lating that posttranscriptional control is an im-portant mechanism for generating appropriatecircadian outputs. For example, the develop-ment of methods to examine nascent transcripts(or pre-mRNAs) around the circadian cyclehave revealed that many rhythmic mRNAs arenot transcribed rhythmically (Koike et al. 2012;Menet et al. 2012) and mathematical modelingof these types of datasets support the idea thatmRNA degradation and other posttranscrip-tional mechanisms must be involved in gener-ating the rhythms in steady-state levels (Lucket al. 2014; Luck and Westermark 2016). Inaddition, a significant fraction of rhythmicproteins is encoded by nonrhythmic mRNAs,suggesting additional regulatory mechanisms(Reddy et al. 2006; Mauvoisin et al. 2014; Robleset al. 2014). It has also been found that the clockis quite insensitive to large fluctuations of tran-scription rate (Dibner et al. 2009), suggestingthat posttranscriptional mechanisms may beable to buffer the system to generate reliablerhythms. Moreover, circadian rhythms can existin red blood cells devoid of nuclei (O’Neill andReddy 2011; O’Neill et al. 2011), showing thatmechanisms beyond transcription can alsodrive rhythmic physiology.

This review will focus on posttranscrip-tional regulatory mechanisms in the circadiansystem in mammals. There are other excellentreviews of circadian posttranscriptional regula-tion in mammals and other organisms (e.g.,Kojima et al. 2011; Staiger and Koster 2011;Zhang et al. 2011; Lim and Allada 2013; Kojimaand Green 2015; Romanowski and Yanovsky2015; Preussner and Heyd 2016).

PROCESSING OF THE PRIMARYTRANSCRIPT

Following transcriptional initiation, DNA-de-pendent RNA polymerase II (Pol II) enters theelongation phase, proceeding down the gene togenerate the nascent RNA transcript. As thenewly synthesized transcript emerges from thepolymerase, processing and modifications be-gin to occur, starting with the addition of the7-methylguanosine cap at the 50 end followed bybinding by the Cap-binding complex (CBC)(reviewed in Carmody and Wente 2009). In-hibiting this process by knockdown of themethylase that generates the 7-methylguano-sine (Rnmt) or the major unit of the CBC(Ncbp1) causes significant lengthening of thecircadian period (.2 h) as measured by lucif-erase reporter under the control of the Bmal1promoter in rhythmic U2OS human osteo-sarcoma cells (Fustin et al. 2013). The mecha-nism by which this lengthens the period isnot known, but suggests that this first step ofmRNA processing must contribute to correctperiodicity.

As the transcript lengthens, any introns thatare present are spliced out shortly after theyemerge from Pol II by the huge ribonucleopro-tein complex called the spliceosome. This stepis extensively regulated and a significant frac-tion of genes can be alternatively spliced, gen-erating more than one (and in some cases,many) different isoforms of the final mRNA.For example, many of the core clock genes havealternative splice forms, as was first reportedfor Clock (King et al. 1997) and Bmal1 whenthey were initially cloned (Ikeda and Nomura1997).

More recently, it was reported that alterna-tive splicing of Per2 in human keratinocytesproduces an extremely short form of PER2called PER2S (Avitabile et al. 2014). This formcontains only the amino-terminal part of thenormal PER2 and is lacking more than half ofthe protein. PER2S is unique from PER2 in thatit is localized to the nucleolus. When nucleolarstructure is transiently and reversibly perturbed,the PER2S is released and resets the clock as seenfrom synchronization of cells following such

C.B. Green

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perturbation. This finding represents a novelmechanism for synchronization in response tonucleolar function.

The first examination of alternative splicingon a genome-wide level across the circadian cy-cle in mammals was performed using exon ar-rays to estimate splice forms from mouse liver(McGlincy et al. 2012). They found alternativesplicing of many exons over the circadian dayand also found changes that were influencedby fasting and feeding, suggesting that this is amechanism used by the clock to regulate thespecific isoforms of mRNAs needed for eachtime of day and for nutrient availability.

Several additional cases have recently beenreported in which alternative transcripts gener-ated by alternative splicing can regulate variousaspects of clock function. For example, it hasbeen found that the Opn4 gene, which encodesthe nonvisual retinal photoreceptor melanop-sin, is alternatively spliced to generate a longand a short isoform, which differ only in theircarboxy-terminal tails (Pires et al. 2009; Jagan-nath et al. 2015). Both isoforms form functionalphotopigments, but mediate different behavio-ral responses to light, presumably through dif-ferent downstream signaling pathways resultingfrom the different carboxyl termini. Althoughboth isoforms contribute to phase shifting,OPN4S is solely responsible for pupillary con-striction and OPN4L regulates negative mask-ing to light.

A particularly intriguing example of rhyth-mic alternative splicing is that reported for theU2af26 gene, which was shown to control PE-RIOD1 protein stability and the circadian clockin mice (Preussner et al. 2014). The alternativesplicing changes the reading frame so the pro-tein encodes a carboxy-terminal domain withsimilarity to the circadian clock protein timelessfrom Drosophila (dTIM). This variant contain-ing the dTIM-like domain interacts with PER1and destabilizes it. Mice lacking U2af26 havedisruption in peripheral rhythms, arrhythmicPER protein levels, and also have rapid phaseadvances to shifted light. This alternative formis both rhythmic and induced acutely by light,and the authors of this paper suggest that alter-native splicing of this gene is a buffering mech-

anism that limits PER1 induction to preventinappropriate phase shifts.

OTHER ALTERNATE TRANSCRIPTS

Functionally analogous to alternative splicing(although not technically “posttranscription-al”), other alternate transcripts can be generatedthrough alternate transcription start site usageor through termination at alternate polyadeny-lation sites. Several examples of this type of reg-ulation have been reported for transcripts in theclock mechanism. In genome-wide analysis oftranscripts from the mouse hypothalamic su-prachiasmatic nucleus (SCN; the locus of thecentral clock in mammals), it was noticed thata previously undescribed exon was expressed inthe Cry1 gene (Pembroke et al. 2015). The in-clusion of this exon adds sequence to the 50 endof the transcript. Both isoforms are rhythmical-ly expressed but cycle in antiphase with eachother. The function of this alternate transcriptis not known.

The decision where to terminate transcrip-tion is also a highly regulated process and ChIP-seq analysis of mouse liver revealed that RNAPol II accumulates at termination sites of the Perand Cry genes, where it interacts with the PE-RIOD repressive complex of proteins during thefirst part of the repressive phase (Padmanabhanet al. 2012). The interaction of the PER complexinhibits SETX, a helicase that promotes tran-scription termination. As levels of the PER com-plex increase, this inhibition prevents normalRNA Pol II release and termination, causingthe polymerase to accumulate near the termi-nation site. Because transcription initiation andtermination are linked, this loss of terminationcauses subsequent loss of initiation, thereforegenerating another negative feedback mecha-nism by the PER complex, but at a posttran-scriptional level.

Alternative polyadenylation site usage isalso used by the circadian system to posttran-scriptionally regulate gene expression. TheRNA-binding proteins CIRBP and RBM3 areboth cold-inducible and their rhythmic expres-sion patterns are driven by the low amplituderhythms in body temperature. Analysis of their

Circadian Posttranscriptional Regulatory Mechanisms

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binding showed that the 30 UTR binding sites areenriched near polyadenylation sites. Depletionof either protein shortened the UTR and coldtemperature (which increases the proteins lev-els) lengthened them (Liu et al. 2013). Changingthe length of the 30 UTR can have profoundimpact on mRNA levels, because this canchange the presence of sites for microRNAs(miRNAs) and RNA-binding proteins that reg-ulate mRNA export, stability, and translation.One of the RNAs bound by CIRBP is the ClockmRNA and knockdown of CIRBP causes re-duced rhythmicity with low amplitude rhythms(Morf et al. 2012). In the knockout, CLOCKprotein levels are low and arrhythmic and ClockmRNA was reduced in the cytoplasm but un-changed in the nucleus, suggesting that CIRBPregulates Clock mRNA nuclear export or pro-motes cytosol-specific decay. Interestingly, itwas recently reported that the threefold rhythmof Cirbp mRNA, driven by the daily smallfluctuation in body temperature, is itself post-transcriptionally generated and is the resultof temperature-dependent regulation of splic-ing efficiency (Gotic et al. 2016). This rhythmin splicing efficiency also affects the accumula-tion of other mRNAs, and represents anotherposttranscriptional mechanism in the circadiantoolbox.

EXPORT FROM THE NUCLEUS

Once the mature mRNA is generated, it must beexported from the nucleus so that it can betranslated in the cytoplasm. The export processis also highly regulated and examples of clockcontrol of this process are beginning to emerge.Evidence that rate of mRNA export contributesto the correct period length determinationcame unexpectedly from experiments probingthe role of transmethylation of mRNA (Fustinet al. 2013). Inhibition of RNA methylation, bythe global inhibitor 3-deazaadenosine or bysuppression of the m6A methylase Mettl3, wasfound to cause prolonged nuclear retention ofcircadian RNAs such as Per2 and Arntl (Bmal1mRNA), independent of transcription. Thisincreased nuclear retention caused decreasedcytoplasmic mRNA and protein levels and pro-

duced long circadian periods in MEF and U2OScells, in SCN slices and in locomotor activity inmice (when inhibitors were infused into thethird ventricle near the SCN). It is unclearfrom these studies whether the circadian length-ening effects of methylation are caused by theslowing of RNA processing at one or more steps(capping, splicing, etc.) or whether this is atargeted effect specifically on mRNA export.However, the long periods caused by inhibitionof the m7 capping are additive with the m6Amethylase inhibition, resulting in extremelylong periods of more than 30 h, suggestingthat these are independent mechanisms bothcontributing to period determination.

Other evidence for circadian control ofnuclear export comes from the demonstrationthat the nuclear bodies called paraspeckles arerhythmic. Paraspeckles are thought to functionto prevent some mRNAs containing specific se-quences (inverted Alu repeats) from being ex-ported from the nucleus and therefore preventtranslation (Chen et al. 2008). These large ribo-nucleoprotein complexes are made from a longnoncoding RNA called Neat1 bound by proteinsincluding NONO, SFPQ, RBM14, and PSPC1.In rat pituitary cells, the numbers of para-speckles and the levels of the RNA and proteincomponents change over the circadian day(Guillaumond et al. 2011; Torres et al. 2016).Furthermore, reporter RNAs containing the in-verted Alu sequences were retained in the nu-cleus and released into the cytoplasm with acorresponding circadian rhythm. The disrup-tion of paraspeckles caused loss of rhythmicityof some mRNAs, therefore showing the im-portance of this mechanism for regulatingrhythmic expression, at least in this cell type.Interestingly, NONO, one of the componentsof the paraspeckles, was originally identified asa PER1-interacting protein in Rat1 fibroblastsand knockdown of this protein in cyclingNIH3T3 cells or in Drosophila caused attenua-tion of rhythms (Brown et al. 2005). Whetherthis is the result of changes in paraspeckles or toother functions of NONO is not known, buttogether these studies support a role for nuclearRNA processing and export in generating prop-er rhythmicity.

C.B. Green




TRANSLATIONAL REGULATION

Once an mRNA is exported from the nucleusand arrives in the cytosol, numerous other reg-ulatory mechanisms determine its fate. SomemRNAs are delivered to specific cellular loca-tions, such as mRNAs that are transported topostsynaptic sites in neurons or to the leadingedge of migrating cells for local translation. Re-gardless of the location, whether or not themRNA is translated is determined by many fac-tors, including signaling pathways that regulatetranslational initiation, levels, and compositionof ribosomes, length of the mRNA poly(A) tailsthat promote circularization and ribosome ini-tiation, the composition of RNA-binding pro-teins and miRNAs that are bound to the mRNA,which can determine the stability of the mRNA.Recent global analysis from proteomic and tran-scriptomic datasets have revealed that there islittle correlation between mRNA levels and pro-tein levels, suggesting that extensive regulationoccurs after the mRNA is synthesized (Vogeland Marcotte 2012). It is clear from a numberof studies that the circadian clock impacts many,if not all, of these steps in the generation of theappropriate rhythmic protein complement ofthe cell.

Comparison of mRNA levels with proteinlevels by transcriptomic and proteomic analysesof mouse liver over the circadian day has re-vealed poor correlation, suggesting extensivecircadian control over translation and/or pro-tein degradation (Reddy et al. 2006; Mauvoisinet al. 2014; Robles et al. 2014). However, prob-lems with the sensitivity of the proteomic anal-ysis only allow the most abundant proteins to bedetected and, therefore, the extent of such reg-ulation was difficult to determine conclusivelyfrom these studies.

Examination of mRNAs bound to poly-somes (and therefore assumed to be activelytranslated) at different times of day found thattranscripts that encoded ribosomal proteinswere preferentially bound to polysomes at thebeginning of night (Jouffe et al. 2013). This cor-responds, in mice, to the beginning of the activephase and feeding phase and these mRNAs con-tained 50 UTR elements called 50-terminal oli-

gopyrimidine (50-TOP) motifs, which are regu-lated by the mammalian target of rapamycin(mTOR) complex 1 in response to nutrient sta-tus. Translation initiation is thought to be therate-limiting step in protein synthesis for mostproteins and this begins with the recognition ofthe 50 cap by eukaryotic initiation factor 4E(eIF4E; which binds as a complex with eIF4Aand eIF4G). eIF4E’s abundance and activityare highly regulated and one of these mecha-nisms is through mTOR-regulated eIF4E-BPs,which prevent eIF4E binding to eIF4G andtherefore prevent the binding to the cap. Indeed,this study found that many of these transla-tion initiation factors, the signaling pathwaysthat regulate them, and the components of themTOR1 complex were all under circadian con-trol in the mouse liver.

Control of translation initiation may be ageneral feature of circadian clocks, because thesepathways are also rhythmic in the mouse SCNand are regulated by light (Cao et al. 2008, 2010,2011; Cao and Obrietan 2010). eIF4E-BP1 ex-pression and phosphorylation are rhythmic inthe SCN and mice lacking Eif4ebp1 entrain tophase shifts more rapidly as measured by loco-motor activity and PER rhythmicity and arealso resistant to desynchrony induced by cons-tant light (Cao et al. 2013). It was also foundthat there was enhanced vasointestinal peptide(VIP) translation in the Eif4ebp1 knockoutmice, suggesting that VIP, a critical neuropep-tide in the SCN, is under translational control bythis mechanism in the SCN. Further analysis ofthis pathway revealed that signaling pathwaysthat phosphorylate eIF4E are also rhythmic inthe SCN and acutely induced by light (Cao etal. 2015). Knockin mice carrying a mutation(S209A) of eIF4E that cannot be phosphorylat-ed were shown to have deficits in phase shiftingand did not entrain well to non-24-h T cycles.Although the precise mechanism for these def-icits are not known, phosphorylation of this sitein eIF4e promotes PER1 and PER2 translationin MEFs and the S209A mutant mice also havereduced levels of PER proteins over the circadi-an cycle and following a light pulse.

Another intriguing link between the mTORpathway and the circadian clock comes from the





demonstration that the core clock transcrip-tional activator BMAL1 has a surprising cyto-solic role as a translation factor (Lipton et al.2015). It was shown that BMAL1 can be phos-phorylated by the mTOR-effector S6K1 and,when phosphorylated, BMAL1 can associatewith the translational machinery and broadlystimulate protein synthesis. These findings di-rectly connect the core circadian timing ma-chinery to the control of protein production.

More extensive analysis of rhythmic trans-lation comes from ribosomal profiling methodsin mouse liver and in rhythmic U2OS cellswith high temporal and nucleotide resolution(Jang et al. 2015; Janich et al. 2015). In themouse liver study (Janich et al. 2015), 150“high-confidence” mRNAs were identified thatwere not rhythmic in their steady-state levelsbut were rhythmically translated and a some-what smaller set with similar profiles were iden-tified in the human U2OS cells. Together, thesestudies suggest that the circadian clock controlstranslation through a number of differentmechanisms and this contributes to the finalrhythmic protein makeup of the cell.

Mathematical modeling of the effect of dif-ferent PER translation kinetics suggested thatregulation of this step could be important forgenerating self-sustained oscillations with char-acteristic period, amplitude, and phase lag (thetime delays between Per mRNA and PER pro-tein) (Nieto et al. 2015). However, both ribo-some profiling studies found that the core clockgenes had matching mRNA and ribosome pro-files, suggesting that the lag between mRNA andprotein peaks over the circadian cycle is not theresult of translational control. However, up-stream open reading frames (uORFs) were iden-tified in several clock genes in both cell types.Because active uORFs usually decrease transla-tion of the downstream main ORF, the presenceof these suggest that these mRNAs may besubject to translational control under some cir-cumstances, for example in response to envi-ronmental signals.

Additionally, a number of studies have im-plicated various RNA-binding proteins andmiRNAs in translational regulation of the coreclock mRNAs and various circadian output

mRNAs. The RNA-binding protein AUF (alsoknown as hnRNP D) is rhythmic and was shownto bind rhythmically to Cry1 30 UTR in anti-phase with peak Cry1 mRNA levels, then asso-ciates with the translation initiation factoreIF3B, recruiting the 40S subunit to 50 end, lead-ing to time-dependent translation of CRY1 (Leeet al. 2014). Another protein, LARK, was shownto bind rhythmically to the Per1 30 UTR andincreases PER1 protein expression, most likelythrough translational regulation (Kojima et al.2003; Kojima et al. 2007). LARK protein levels(but not mRNA levels) cycle in the SCN andknockdown or overexpression of this gene incycling cells produces short or long periods, re-spectively. Per1 undergoes both cap-dependentand IRES-mediated translation and the proteinhnRNP Q has been reported to control time-dependent IRES-mediated translation of Per1through rhythmic interaction with the Per1mRNA (Lee et al. 2012a,b) and to regulate thetranslation of AANAT, the rate-limiting enzymein melatonin production in the pineal gland(Kim et al. 2007).

Another potential role for translational reg-ulation is suggested by the phenotypes of micelacking the genes for the translational repressorproteins, Fmr1 (encodes FMRP) and Fxr2(Zhang et al. 2008). In mice, knockout of eitherFmr1 or Fxr2 have short periods and Fmr1/Fxr2double knockouts (both homo- and heterozy-gous) are arrhythmic. The mechanism behindthis is not known and although they did seechanges in several core clock gene mRNA levelsin liver; this study did not examine the levels ofthese proteins, so no conclusion about transla-tional control can be drawn.

Several RNA-binding proteins have alsobeen identified that contribute to the circadianregulation of mRNA half-life, which can indi-rectly impact translation. These include AUF1,which modulates Cry1 stability (Woo et al.2010), polypyrimidine tract-binding protein(PTB), which binds to Per2 30 UTR and regu-lates its stability (Woo et al. 2009), KSRP, whichregulates the stability of Per2 (Chou et al. 2015),and AUF1 and hnRNP K, which both interactwith Per3 30 UTR but have opposite effects, withhnRNP K stabilizing the mRNA and AUF1 de-

C.B. Green




stabilizing it (Kim et al. 2015). In addition,hnRNP Q, hnRNP R, and hnRNP L have allbeen shown to be expressed rhythmically inthe pineal gland and induce the degradationof the mRNA encoding AANAT (Kim et al.2005, 2007).

miRNAs

In addition to the many RNA-binding proteinsthat regulate translation and mRNA decay,miRNAs also play a critical role. And they tooappear to play a role in shaping the circadianproteome. A number of miRNAs have been im-plicated in the regulation of specific mRNAs,including the highly abundant, liver-specificmiRNA-122, which is synthesized rhythmicallyunder the control of the circadian transcrip-tional repressor Rev-erba, although the levelsof the mature form are not rhythmic becauseof its long half-life. Knockdown of this miRNAresults in both increases and decreases of hun-dreds of mRNAs, a large fraction of which arerhythmic. These include mRNAs encodingproteins in many important metabolic path-ways in the liver, including lipid and cholesterolmetabolism (Gatfield et al. 2009). Among thesemRNA targets is the mRNA encoding Noctur-nin, an enzyme that removes poly(A) tails frommRNAs and is itself involved in circadian post-transcriptional regulation (Kojima et al. 2010).

There are a number of other examples ofspecific miRNAs that are involved in circadianrhythms, including the brain-specific miRNAsmiR-219 and miR-132, which appear to con-tribute to both light-induced clock resettingand period length regulation (Cheng et al.2007; Alvarez-Saavedra et al. 2011), miR-155in macrophages, which targets the 30 UTR ofBMAL1 (Curtis et al. 2015), miR-185, whichoscillates in antiphase to CRY1 levels and con-trols Cry1 mRNA translation in NIH3T3 cells(Lee et al. 2013).

Despite these examples of specific miRNAsregulating core clock genes, the effects ofmiRNAs on the clock is less clear when globalmiRNA biogenesis is prevented by Dicer knock-down. In liver, using an inducible Dicer knock-down system, extensive changes in rhythmic

mRNA profiles are seen, but these changes arelargely modulatory, such as changes in phase oramplitude (Du et al. 2014). The core clock genemRNAs were largely not affected by miRNA lossexcept for Per2, which showed a twofold in-crease in amplitude. Liver explants from thesemice had slight period lengthening. In contrast,knockdown of Dicer in NIH3T3 cells increasedthe Cry1 30 UTR reporter activity (Lee et al.2013) and Dicer knockdown in mouse embryofibroblast cells produced short periods, whichwas attributed to faster Per1 and Per2 translation(Chen et al. 2013). Since such different resultshave been noted in these different cell types,it may be that miRNAs are important for tis-sue-specific tuning and shaping of circadiangene-expression patterns, and perhaps couldcontribute to known tissue-specific differencesin phases and free-running period lengths (Yooet al. 2004).

POLY(A) TAIL LENGTH

One of the first observations of circadian post-transcriptional control in mammals was the ob-servation that the arginine vasopressin (AVP)mRNA changed size over the circadian day inthe SCN (Robinson et al. 1988). This change insize was shown to be caused by changes in thelength of the poly(A) tails at the 30 ends of themRNA. Long poly(A) tails are added to mRNAsin the nucleus following transcription termina-tion and shortening and removal of the tails byenzymes called deadenylases is a critical step indegradation of the mRNA and is regulated byRNA-binding proteins and miRNAs (Eckmannet al. 2011). Although it was originally thoughtthat shortening the tails determined decay, it isnow known that some mRNAs can exist inshort-tailed forms and be readenylated in thecytoplasm by cytoplasmic poly(A) polymerases(reviewed in Weill et al. 2012). Circadian profil-ing of poly(A) tail lengths from mouse liversamples revealed that hundreds of mRNAshave rhythmic poly(A) tail lengths and thatthese lengths correlate well with protein levelsencoded by those mRNAs, even when themRNAs were not rhythmic at the steady-statelevel (Kojima et al. 2012). Proteins implicated in





cytoplasmic polyadenylation were also found tobe rhythmic in the mouse liver and one of these,CPEB2, was found to regulate rhythmic poly(A)addition for at least some mRNAs. Althoughpoly(A) tail length has not been found tostrongly correlate with translatability in general,it can regulate translation in certain cases weretranscriptional control is not useful such as inthe early embryo or in the postsynaptic regionof neurons (Subtelny et al. 2014). The strongcorrelation between poly(A) tail length and pro-tein rhythms in the mouse liver suggest that thecircadian system is another case in which thismechanism is used.

There are at least eight deadenylases inmammals (Goldstrohm and Wickens 2008)and several of them show low amplituderhythms, peaking in the early day (Kojima etal. 2012). However, one of them, the deadeny-lase called Nocturnin (Baggs and Green 2003;Garbarino-Pico et al. 2007), shows very highamplitude rhythms, peaking at night (Greenand Besharse 1996; Wang et al. 2001; Stubble-field et al. 2012; Godwin et al. 2013). Mice lack-ing Nocturnin have a strong metabolic pheno-type, with protection from obesity on a high-fatdiet and alterations in many circadian metabolicpathways (Green et al. 2007; Douris and Green2008; Douris et al. 2011; Stubblefield et al.2012). Comparison of poly(A) tail lengths, us-ing an approach similar to the one describedabove for the circadian analysis, revealedmRNAs with longer tails in the Nocturninknockout liver and these represent candidatesfor Nocturnin target mRNAs (Kojima et al.2015). Surprisingly, these mRNAs showed littleoverlap with the set of mRNAs with cyclingpoly(A) tail lengths or with the known rhythmicmRNAs, suggesting that the role of Nocturnin isnot to generate rhythmic tails. However, the as-say used to identify the poly(A) tail lengths inboth experiments (differential elution from oli-go[dT] beads) could not reliably detect mRNAsthat are present at low copy number. More workwith more sensitive assays is needed to definethe role for Nocturnin in the circadian clock.

Finally, the role of cytoplasmic granulessuch as processing bodies (P-bodies) in regulat-ing circadian protein expression has not been

carefully examined, but they are likely to be in-volved. These bodies store mRNAs that are notbeing translated (such as those that have beendeadenylated) until they are either degraded orplaced back into the translatable pool (Deckerand Parker 2012). Recent ribosome profiling ofU2OS cells revealed that the LSM1 protein, acritical component of P-bodies is rhythmicallytranslated and subsequent experiments showedthat cytoplasmic P-body formation is rhythmicin these cells (Jang et al. 2015). This findingprovides further evidence that the circadianclock governs the fate of mRNAs in the cyto-plasm in previously unappreciated ways.

CONCLUDING REMARKS

Circadian rhythms regulate critical functionsthroughout the mammalian body, includingbiochemical and metabolic pathways, higher or-der cell and tissue functions, and complex be-havior. These functions are generated by therhythmic patterns of protein function (notmRNA levels) and the emerging data discussedhere indicate that posttranscriptional regulatorymechanisms are not simply “refinements” oftranscriptional regulation, but are critical forgenerating the proper rhythmic protein outputsof the clock. Despite these exciting new insights,it is clear that there is much more to be learnedabout how the clock uses posttranscriptionalmechanisms to drive rhythmic physiology.

ACKNOWLEDGMENTS

I thank the National Institutes of Health (NIH)for funding support (R01 GM112991, R01GM111387, and R01 AG045795).

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