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Circadian Posttranscriptional Regulatory Mechanisms in

Carla B. Green

Department of , University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111 Correspondence: [email protected]

The drives rhythms in the levels of thousands of in the mammalian , arising in part from rhythmic transcriptional regulation of the that encode them. However, recent evidence has shown that posttranscriptional processes also play a major role in generating the rhythmic makeup and ultimately the rhythmic of the cell. Regulation of steps throughout the life of the messenger RNA (mRNA), ranging from initial mRNA processing and export from the nucleus to extensive control of and degradation in the cytosol have been shown to be important for producing the final rhythms in protein levels critical for proper circadian rhythmicity. These findings will be reviewed here.

n mammals, cell-autonomous circadian clocks core clock mechanism, or indirectly by other Icontrol rhythmic expression of thousands of rhythmic transcription factors that are down- messenger RNAs (mRNAs), ultimately generat- stream from the core loop. However, many steps ing daily rhythms in , physiology, occur between transcriptional initiation and ul- and behavior (Pittendrigh 1981a,b; Akhtar et al. timate protein function and many, if not all, of 2002; Panda et al. 2002; Storch et al. 2002; Ueda these steps could conceivably be subject to cir- et al. 2002; Duffield 2003; Welsh et al. 2004; cadian regulation. Reddy et al. 2006). This dynamic control of Transcripts are capped and spliced while expression is a hallmark of the mammalian they are still being transcribed and then the 30 circadian clock, which is comprised of inter- ends are cleaved and polyadenylated. Each of locking transcriptional–translational these steps requires many accessory proteins loops (Lowrey and Takahashi 2004; Takahashi and/or small RNAs and frequently many alter- et al. 2008). Steady-state levels of 5%–10% of nate splice forms and alternate the mRNAs in any given are rhythmic sites can be chosen. RNAs are coated with RNA- (Duffield 2003; Rey et al. 2011; Koike et al. binding proteins, forming ribonucleoprotein 2012; Menet et al. 2012). Many of these genes complexes and are exported to the cytoplasm are regulated transcriptionally, either by direct (and in some cases to specific regions of the rhythmic transactivation by CLOCK/BMAL1, cell), where they are translated and eventually the central transcriptional activators of the degraded. During the time in the cytoplasm, the

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mRNAs may be deadenylated and stored in a PROCESSING OF THE PRIMARY translationally silent form, followed by later TRANSCRIPT readenylation to make them translationally competent. Regulation of the protein products Following transcriptional initiation, DNA-de- that result from translating these mRNAs de- pendent RNA polymerase II (Pol II) enters the pends on extensive regulation at many or all of elongation phase, proceeding down the gene to these steps. generate the nascent RNA transcript. As the Much of the work on the mechanisms of newly synthesized transcript emerges from the circadian has focused on tran- polymerase, processing and modifications be- scriptional control and the primary readouts gin to occur, starting with the addition of the have been steady-state mRNA levels, as a result 7-methylguanosine cap at the 50 end followed by largely of the ease of making these measure- binding by the Cap-binding complex (CBC) ments. However, extensive evidence is accumu- (reviewed in Carmody and Wente 2009). In- lating that posttranscriptional control is an im- hibiting this process by knockdown of the portant mechanism for generating appropriate methylase that generates the 7-methylguano- circadian outputs. For example, the develop- sine (Rnmt) or the major unit of the CBC ment of methods to examine nascent transcripts (Ncbp1) causes significant lengthening of the (or pre-mRNAs) around the circadian cycle circadian period (.2 h) as measured by lucif- have revealed that many rhythmic mRNAs are erase reporter under the control of the Bmal1 not transcribed rhythmically (Koike et al. 2012; promoter in rhythmic U2OS human osteo- Menet et al. 2012) and mathematical modeling sarcoma cells (Fustin et al. 2013). The mecha- of these types of datasets support the idea that nism by which this lengthens the period is mRNA degradation and other posttranscrip- not known, but suggests that this first step of tional mechanisms must be involved in gener- mRNA processing must contribute to correct ating the rhythms in steady-state levels (Luck periodicity. et al. 2014; Luck and Westermark 2016). In As the transcript lengthens, any introns that addition, a significant fraction of rhythmic are present are spliced out shortly after they proteins is encoded by nonrhythmic mRNAs, emerge from Pol II by the huge ribonucleopro- suggesting additional regulatory mechanisms tein complex called the spliceosome. This step (Reddy et al. 2006; Mauvoisin et al. 2014; Robles is extensively regulated and a significant frac- et al. 2014). It has also been found that the clock tion of genes can be alternatively spliced, gen- is quite insensitive to large fluctuations of tran- erating more than one (and in some cases, scription rate (Dibner et al. 2009), suggesting many) different isoforms of the final mRNA. that posttranscriptional mechanisms may be For example, many of the core clock genes have able to buffer the system to generate reliable alternative splice forms, as was first reported rhythms. Moreover, circadian rhythms can exist for Clock (King et al. 1997) and Bmal1 when in red blood cells devoid of nuclei (O’Neill and they were initially cloned (Ikeda and Nomura Reddy 2011; O’Neill et al. 2011), showing that 1997). mechanisms beyond transcription can also More recently, it was reported that alterna- drive rhythmic physiology. tive splicing of Per2 in human keratinocytes This review will focus on posttranscrip- produces an extremely short form of PER2 tional regulatory mechanisms in the circadian called PER2S (Avitabile et al. 2014). This form system in mammals. There are other excellent contains only the amino-terminal part of the reviews of circadian posttranscriptional regula- normal PER2 and is lacking more than half of tion in mammals and other (e.g., the protein. PER2S is unique from PER2 in that Kojima et al. 2011; Staiger and Koster 2011; it is localized to the nucleolus. When nucleolar Zhang et al. 2011; Lim and Allada 2013; Kojima structure is transiently and reversibly perturbed, and Green 2015; Romanowski and Yanovsky the PER2S is released and resets the clock as seen 2015; Preussner and Heyd 2016). from synchronization of cells following such

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Circadian Posttranscriptional Regulatory Mechanisms

perturbation. This finding represents a novel anism that limits PER1 induction to prevent mechanism for synchronization in response to inappropriate phase shifts. nucleolar function. The first examination of alternative splicing OTHER ALTERNATE TRANSCRIPTS on a genome-wide level across the circadian cy- cle in mammals was performed using exon ar- Functionally analogous to alternative splicing rays to estimate splice forms from mouse (although not technically “posttranscription- (McGlincy et al. 2012). They found alternative al”), other alternate transcripts can be generated splicing of many exons over the circadian day through alternate transcription start site usage and also found changes that were influenced or through termination at alternate polyadeny- by fasting and feeding, suggesting that this is a lation sites. Several examples of this type of reg- mechanism used by the clock to regulate the ulation have been reported for transcripts in the specific isoforms of mRNAs needed for each clock mechanism. In genome-wide analysis of time of day and for nutrient availability. transcripts from the mouse hypothalamic su- Several additional cases have recently been prachiasmatic nucleus (SCN; the locus of the reported in which alternative transcripts gener- central clock in mammals), it was noticed that ated by alternative splicing can regulate various a previously undescribed exon was expressed in aspects of clock function. For example, it has the Cry1 gene (Pembroke et al. 2015). The in- been found that the Opn4 gene, which encodes clusion of this exon adds sequence to the 50 end the nonvisual retinal photoreceptor melanop- of the transcript. Both isoforms are rhythmical- sin, is alternatively spliced to generate a long ly expressed but cycle in antiphase with each and a short isoform, which differ only in their other. The function of this alternate transcript carboxy-terminal tails (Pires et al. 2009; Jagan- is not known. nath et al. 2015). Both isoforms form functional The decision where to terminate transcrip- photopigments, but mediate different behavio- tion is also a highly regulated process and ChIP- ral responses to light, presumably through dif- seq analysis of mouse liver revealed that RNA ferent downstream signaling pathways resulting Pol II accumulates at termination sites of the Per from the different carboxyl termini. Although and Cry genes, where it interacts with the PE- both isoforms contribute to phase shifting, RIOD repressive complex of proteins during the OPN4S is solely responsible for pupillary con- first part of the repressive phase (Padmanabhan striction and OPN4L regulates negative mask- et al. 2012). The interaction of the PER complex ing to light. inhibits SETX, a helicase that promotes tran- A particularly intriguing example of rhyth- scription termination. As levels of the PER com- mic alternative splicing is that reported for the plex increase, this inhibition prevents normal U2af26 gene, which was shown to control PE- RNA Pol II release and termination, causing RIOD1 protein stability and the circadian clock the polymerase to accumulate near the termi- in mice (Preussner et al. 2014). The alternative nation site. Because transcription initiation and splicing changes the reading frame so the pro- termination are linked, this loss of termination tein encodes a carboxy-terminal domain with causes subsequent loss of initiation, therefore similarity to the circadian clock protein timeless generating another negative feedback mecha- from Drosophila (dTIM). This variant contain- nism by the PER complex, but at a posttran- ing the dTIM-like domain interacts with PER1 scriptional level. and destabilizes it. Mice lacking U2af26 have Alternative polyadenylation site usage is disruption in peripheral rhythms, arrhythmic also used by the circadian system to posttran- PER protein levels, and also have rapid phase scriptionally regulate gene expression. The advances to shifted light. This alternative form RNA-binding proteins CIRBP and RBM3 are is both rhythmic and induced acutely by light, both cold-inducible and their rhythmic expres- and the authors of this paper suggest that alter- sion patterns are driven by the low amplitude native splicing of this gene is a buffering mech- rhythms in body temperature. Analysis of their

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binding showed that the 30 UTR binding sites are duced long circadian periods in MEF and U2OS enriched near polyadenylation sites. Depletion cells, in SCN slices and in locomotor activity in of either protein shortened the UTR and cold mice (when inhibitors were infused into the temperature (which increases the proteins lev- third ventricle near the SCN). It is unclear els) lengthened them (Liu et al. 2013). Changing from these studies whether the circadian length- the length of the 30 UTR can have profound ening effects of methylation are caused by the impact on mRNA levels, because this can slowing of RNA processing at one or more steps change the presence of sites for microRNAs (capping, splicing, etc.) or whether this is a (miRNAs) and RNA-binding proteins that reg- targeted effect specifically on mRNA export. ulate mRNA export, stability, and translation. However, the long periods caused by inhibition One of the RNAs bound by CIRBP is the Clock of the m7 capping are additive with the m6A mRNA and knockdown of CIRBP causes re- methylase inhibition, resulting in extremely duced rhythmicity with low amplitude rhythms long periods of more than 30 h, suggesting (Morf et al. 2012). In the knockout, CLOCK that these are independent mechanisms both protein levels are low and arrhythmic and Clock contributing to period determination. mRNA was reduced in the cytoplasm but un- Other evidence for circadian control of changed in the nucleus, suggesting that CIRBP nuclear export comes from the demonstration regulates Clock mRNA nuclear export or pro- that the nuclear bodies called paraspeckles are motes cytosol-specific decay. Interestingly, it rhythmic. Paraspeckles are thought to function was recently reported that the threefold rhythm to prevent some mRNAs containing specific se- of Cirbp mRNA, driven by the daily small quences (inverted Alu repeats) from being ex- fluctuation in body temperature, is itself post- ported from the nucleus and therefore prevent transcriptionally generated and is the result translation (Chen et al. 2008). These large ribo- of temperature-dependent regulation of splic- nucleoprotein complexes are made from a long ing efficiency (Gotic et al. 2016). This rhythm noncoding RNA called Neat1 bound by proteins in splicing efficiency also affects the accumula- including NONO, SFPQ, RBM14, and PSPC1. tion of other mRNAs, and represents another In rat pituitary cells, the numbers of para- posttranscriptional mechanism in the circadian speckles and the levels of the RNA and protein toolbox. components change over the circadian day (Guillaumond et al. 2011; Torres et al. 2016). Furthermore, reporter RNAs containing the in- EXPORT FROM THE NUCLEUS verted Alu sequences were retained in the nu- Once the mature mRNA is generated, it must be cleus and released into the cytoplasm with a exported from the nucleus so that it can be corresponding . The disrup- translated in the cytoplasm. The export process tion of paraspeckles caused loss of rhythmicity is also highly regulated and examples of clock of some mRNAs, therefore showing the im- control of this process are beginning to emerge. portance of this mechanism for regulating Evidence that rate of mRNA export contributes rhythmic expression, at least in this cell type. to the correct period length determination Interestingly, NONO, one of the components came unexpectedly from experiments probing of the paraspeckles, was originally identified as the role of transmethylation of mRNA (Fustin a PER1-interacting protein in Rat1 fibroblasts et al. 2013). Inhibition of RNA methylation, by and knockdown of this protein in cycling the global inhibitor 3-deazaadenosine or by NIH3T3 cells or in Drosophila caused attenua- suppression of the m6A methylase Mettl3, was tion of rhythms (Brown et al. 2005). Whether found to cause prolonged nuclear retention of this is the result of changes in paraspeckles or to circadian RNAs such as Per2 and Arntl (Bmal1 other functions of NONO is not known, but mRNA), independent of transcription. This together these studies support a role for nuclear increased nuclear retention caused decreased RNA processing and export in generating prop- cytoplasmic mRNA and protein levels and pro- er rhythmicity.

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TRANSLATIONAL REGULATION gopyrimidine (50-TOP) motifs, which are regu- lated by the mammalian target of rapamycin Once an mRNA is exported from the nucleus (mTOR) complex 1 in response to nutrient sta- and arrives in the cytosol, numerous other reg- tus. Translation initiation is thought to be the ulatory mechanisms determine its fate. Some rate-limiting step in protein synthesis for most mRNAs are delivered to specific cellular loca- proteins and this begins with the recognition of tions, such as mRNAs that are transported to the 50 cap by eukaryotic initiation factor 4E postsynaptic sites in neurons or to the leading (eIF4E; which binds as a complex with eIF4A edge of migrating cells for local translation. Re- and eIF4G). eIF4E’s abundance and activity gardless of the location, whether or not the are highly regulated and one of these mecha- mRNA is translated is determined by many fac- nisms is through mTOR-regulated eIF4E-BPs, tors, including signaling pathways that regulate which prevent eIF4E binding to eIF4G and translational initiation, levels, and composition therefore prevent the binding to the cap. Indeed, of ribosomes, length of the mRNA poly(A) tails this study found that many of these transla- that promote circularization and ribosome ini- tion initiation factors, the signaling pathways tiation, the composition of RNA-binding pro- that regulate them, and the components of the teins and miRNAs that are bound to the mRNA, mTOR1 complex were all under circadian con- which can determine the stability of the mRNA. trol in the mouse liver. Recent global analysis from proteomic and tran- Control of translation initiation may be a scriptomic datasets have revealed that there is general feature of circadian clocks, because these little correlation between mRNA levels and pro- pathways are also rhythmic in the mouse SCN tein levels, suggesting that extensive regulation and are regulated by light (Cao et al. 2008, 2010, occurs after the mRNA is synthesized (Vogel 2011; Cao and Obrietan 2010). eIF4E-BP1 ex- and Marcotte 2012). It is clear from a number pression and phosphorylation are rhythmic in of studies that the circadian clock impacts many, the SCN and mice lacking Eif4ebp1 entrain to if not all, of these steps in the generation of the phase shifts more rapidly as measured by loco- appropriate rhythmic protein complement of motor activity and PER rhythmicity and are the cell. also resistant to desynchrony induced by cons- Comparison of mRNA levels with protein tant light (Cao et al. 2013). It was also found levels by transcriptomic and proteomic analyses that there was enhanced vasointestinal peptide of mouse liver over the circadian day has re- (VIP) translation in the Eif4ebp1 knockout vealed poor correlation, suggesting extensive mice, suggesting that VIP, a critical neuropep- circadian control over translation and/or pro- tide in the SCN, is under translational control by tein degradation (Reddy et al. 2006; Mauvoisin this mechanism in the SCN. Further analysis of et al. 2014; Robles et al. 2014). However, prob- this pathway revealed that signaling pathways lems with the sensitivity of the proteomic anal- that phosphorylate eIF4E are also rhythmic in ysis only allow the most abundant proteins to be the SCN and acutely induced by light (Cao et detected and, therefore, the extent of such reg- al. 2015). Knockin mice carrying a mutation ulation was difficult to determine conclusively (S209A) of eIF4E that cannot be phosphorylat- from these studies. ed were shown to have deficits in phase shifting Examination of mRNAs bound to poly- and did not entrain well to non-24-h T cycles. somes (and therefore assumed to be actively Although the precise mechanism for these def- translated) at different times of day found that icits are not known, phosphorylation of this site transcripts that encoded ribosomal proteins in eIF4e promotes PER1 and PER2 translation were preferentially bound to polysomes at the in MEFs and the S209A mutant mice also have beginning of night (Jouffe et al. 2013). This cor- reduced levels of PER proteins over the circadi- responds, in mice, to the beginning of the active an cycle and following a light pulse. phase and feeding phase and these mRNAs con- Another intriguing link between the mTOR tained 50 UTR elements called 50-terminal oli- pathway and the circadian clock comes from the

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demonstration that the core clock transcrip- mRNAs. The RNA-binding protein AUF (also tional activator BMAL1 has a surprising cyto- known as hnRNP D) is rhythmic and was shown solic role as a translation factor (Lipton et al. to bind rhythmically to Cry1 30 UTR in anti- 2015). It was shown that BMAL1 can be phos- phase with peak Cry1 mRNA levels, then asso- phorylated by the mTOR-effector S6K1 and, ciates with the translation initiation factor when phosphorylated, BMAL1 can associate eIF3B, recruiting the 40S subunit to 50 end, lead- with the translational machinery and broadly ing to time-dependent translation of CRY1 (Lee stimulate protein synthesis. These findings di- et al. 2014). Another protein, LARK, was shown rectly connect the core circadian timing ma- to bind rhythmically to the Per1 30 UTR and chinery to the control of protein production. increases PER1 protein expression, most likely More extensive analysis of rhythmic trans- through translational regulation (Kojima et al. lation comes from ribosomal profiling methods 2003; Kojima et al. 2007). LARK protein levels in mouse liver and in rhythmic U2OS cells (but not mRNA levels) cycle in the SCN and with high temporal and nucleotide resolution knockdown or overexpression of this gene in (Jang et al. 2015; Janich et al. 2015). In the cycling cells produces short or long periods, re- mouse liver study (Janich et al. 2015), 150 spectively. Per1 undergoes both cap-dependent “high-confidence” mRNAs were identified that and IRES-mediated translation and the protein were not rhythmic in their steady-state levels hnRNP Q has been reported to control time- but were rhythmically translated and a some- dependent IRES-mediated translation of Per1 what smaller set with similar profiles were iden- through rhythmic interaction with the Per1 tified in the human U2OS cells. Together, these mRNA (Lee et al. 2012a,b) and to regulate the studies suggest that the circadian clock controls translation of AANAT, the rate-limiting enzyme translation through a number of different in melatonin production in the pineal gland mechanisms and this contributes to the final (Kim et al. 2007). rhythmic protein makeup of the cell. Another potential role for translational reg- Mathematical modeling of the effect of dif- ulation is suggested by the of mice ferent PER translation kinetics suggested that lacking the genes for the translational regulation of this step could be important for proteins, Fmr1 (encodes FMRP) and Fxr2 generating self-sustained oscillations with char- (Zhang et al. 2008). In mice, knockout of either acteristic period, amplitude, and phase lag (the Fmr1 or Fxr2 have short periods and Fmr1/Fxr2 time delays between Per mRNA and PER pro- double knockouts (both homo- and heterozy- tein) (Nieto et al. 2015). However, both ribo- gous) are arrhythmic. The mechanism behind some profiling studies found that the core clock this is not known and although they did see genes had matching mRNA and ribosome pro- changes in several core clock gene mRNA levels files, suggesting that the lag between mRNA and in liver; this study did not examine the levels of protein peaks over the circadian cycle is not the these proteins, so no conclusion about transla- result of translational control. However, up- tional control can be drawn. stream open reading frames (uORFs) were iden- Several RNA-binding proteins have also tified in several clock genes in both cell types. been identified that contribute to the circadian Because active uORFs usually decrease transla- regulation of mRNA half-life, which can indi- tion of the downstream main ORF,the presence rectly impact translation. These include AUF1, of these suggest that these mRNAs may be which modulates Cry1 stability (Woo et al. subject to translational control under some cir- 2010), polypyrimidine tract-binding protein cumstances, for example in response to envi- (PTB), which binds to Per2 30 UTR and regu- ronmental signals. lates its stability (Woo et al. 2009), KSRP,which Additionally, a number of studies have im- regulates the stability of Per2 (Chou et al. 2015), plicated various RNA-binding proteins and and AUF1 and hnRNP K, which both interact miRNAs in translational regulation of the core with Per3 30 UTR but have opposite effects, with clock mRNAs and various circadian output hnRNP K stabilizing the mRNA and AUF1 de-

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stabilizing it (Kim et al. 2015). In addition, mRNA profiles are seen, but these changes are hnRNP Q, hnRNP R, and hnRNP L have all largely modulatory, such as changes in phase or been shown to be expressed rhythmically in amplitude (Du et al. 2014). The core clock gene the pineal gland and induce the degradation mRNAs were largely not affected by miRNA loss of the mRNA encoding AANAT (Kim et al. except for Per2, which showed a twofold in- 2005, 2007). crease in amplitude. Liver explants from these mice had slight period lengthening. In contrast, knockdown of Dicer in NIH3T3 cells increased miRNAs the Cry130 UTR reporter activity (Lee et al. In addition to the many RNA-binding proteins 2013) and Dicer knockdown in mouse embryo that regulate translation and mRNA decay, fibroblast cells produced short periods, which miRNAs also play a critical role. And they too was attributed to faster Per1 and Per2 translation appear to play a role in shaping the circadian (Chen et al. 2013). Since such different results proteome. A number of miRNAs have been im- have been noted in these different cell types, plicated in the regulation of specific mRNAs, it may be that miRNAs are important for tis- including the highly abundant, liver-specific sue-specific tuning and shaping of circadian miRNA-122, which is synthesized rhythmically gene-expression patterns, and perhaps could under the control of the circadian transcrip- contribute to known tissue-specific differences tional repressor Rev-erba, although the levels in phases and free-running period lengths (Yoo of the mature form are not rhythmic because et al. 2004). of its long half-life. Knockdown of this miRNA results in both increases and decreases of hun- POLY(A) TAIL LENGTH dreds of mRNAs, a large fraction of which are rhythmic. These include mRNAs encoding One of the first observations of circadian post- proteins in many important metabolic path- transcriptional control in mammals was the ob- ways in the liver, including lipid and cholesterol servation that the arginine vasopressin (AVP) (Gatfield et al. 2009). Among these mRNA changed size over the circadian day in mRNA targets is the mRNA encoding Noctur- the SCN (Robinson et al. 1988). This change in nin, an enzyme that removes poly(A) tails from size was shown to be caused by changes in the mRNAs and is itself involved in circadian post- length of the poly(A) tails at the 30 ends of the transcriptional regulation (Kojima et al. 2010). mRNA. Long poly(A) tails are added to mRNAs There are a number of other examples of in the nucleus following transcription termina- specific miRNAs that are involved in circadian tion and shortening and removal of the tails by rhythms, including the brain-specific miRNAs enzymes called deadenylases is a critical step in miR-219 and miR-132, which appear to con- degradation of the mRNA and is regulated by tribute to both light-induced clock resetting RNA-binding proteins and miRNAs (Eckmann and period length regulation (Cheng et al. et al. 2011). Although it was originally thought 2007; Alvarez-Saavedra et al. 2011), miR-155 that shortening the tails determined decay, it is in macrophages, which targets the 30 UTR of now known that some mRNAs can exist in BMAL1 (Curtis et al. 2015), miR-185, which short-tailed forms and be readenylated in the oscillates in antiphase to CRY1 levels and con- cytoplasm by cytoplasmic poly(A) polymerases trols Cry1 mRNA translation in NIH3T3 cells (reviewed in Weill et al. 2012). Circadian profil- (Lee et al. 2013). ing of poly(A) tail lengths from mouse liver Despite these examples of specific miRNAs samples revealed that hundreds of mRNAs regulating core clock genes, the effects of have rhythmic poly(A) tail lengths and that miRNAs on the clock is less clear when global these lengths correlate well with protein levels miRNA biogenesis is prevented by Dicer knock- encoded by those mRNAs, even when the down. In liver, using an inducible Dicer knock- mRNAs were not rhythmic at the steady-state down system, extensive changes in rhythmic level (Kojima et al. 2012). Proteins implicated in

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cytoplasmic polyadenylation were also found to carefully examined, but they are likely to be in- be rhythmic in the mouse liver and one of these, volved. These bodies store mRNAs that are not CPEB2, was found to regulate rhythmic poly(A) being translated (such as those that have been addition for at least some mRNAs. Although deadenylated) until they are either degraded or poly(A) tail length has not been found to placed back into the translatable pool (Decker strongly correlate with translatability in general, and Parker 2012). Recent ribosome profiling of it can regulate translation in certain cases were U2OS cells revealed that the LSM1 protein, a transcriptional control is not useful such as in critical component of P-bodies is rhythmically the early embryo or in the postsynaptic region translated and subsequent experiments showed of neurons (Subtelny et al. 2014). The strong that cytoplasmic P-body formation is rhythmic correlation between poly(A) tail length and pro- in these cells (Jang et al. 2015). This finding tein rhythms in the mouse liver suggest that the provides further evidence that the circadian circadian system is another case in which this clock governs the fate of mRNAs in the cyto- mechanism is used. plasm in previously unappreciated ways. There are at least eight deadenylases in mammals (Goldstrohm and Wickens 2008) CONCLUDING REMARKS and several of them show low amplitude rhythms, peaking in the early day (Kojima et Circadian rhythms regulate critical functions al. 2012). However, one of them, the deadeny- throughout the mammalian body, including lase called (Baggs and Green 2003; biochemical and metabolic pathways, higher or- Garbarino-Pico et al. 2007), shows very high der cell and tissue functions, and complex be- amplitude rhythms, peaking at night (Green havior. These functions are generated by the and Besharse 1996; Wang et al. 2001; Stubble- rhythmic patterns of protein function (not field et al. 2012; Godwin et al. 2013). Mice lack- mRNA levels) and the emerging data discussed ing Nocturnin have a strong metabolic pheno- here indicate that posttranscriptional regulatory type, with protection from obesity on a high-fat mechanisms are not simply “refinements” of diet and alterations in many circadian metabolic transcriptional regulation, but are critical for pathways (Green et al. 2007; Douris and Green generating the proper rhythmic protein outputs 2008; Douris et al. 2011; Stubblefield et al. of the clock. Despite these exciting new insights, 2012). Comparison of poly(A) tail lengths, us- it is clear that there is much more to be learned ing an approach similar to the one described about how the clock uses posttranscriptional above for the circadian analysis, revealed mechanisms to drive rhythmic physiology. mRNAs with longer tails in the Nocturnin knockout liver and these represent candidates ACKNOWLEDGMENTS for Nocturnin target mRNAs (Kojima et al. 2015). Surprisingly, these mRNAs showed little I thank the National Institutes of Health (NIH) overlap with the set of mRNAs with cycling for funding support (R01 GM112991, R01 poly(A) tail lengths or with the known rhythmic GM111387, and R01 AG045795). mRNAs, suggesting that the role of Nocturnin is not to generate rhythmic tails. However, the as- say used to identify the poly(A) tail lengths in REFERENCES both experiments (differential elution from oli- Akhtar RA, Reddy AB, Maywood ES, Clayton JD, King VM, go[dT] beads) could not reliably detect mRNAs Smith AG, Gant TW, Hastings MH, Kyriacou CP. 2002. Circadian cycling of the mouse liver transcriptome, as that are present at low copy number. More work revealed by cDNA microarray, is driven by the suprachi- with more sensitive assays is needed to define asmatic nucleus. Curr Biol 12: 540–550. the role for Nocturnin in the circadian clock. Alvarez-Saavedra M, Antoun G, Yanagiya A, Oliva-Hernan- Finally, the role of cytoplasmic granules dez R, Cornejo-Palma D, Perez-Iratxeta C, Sonenberg N, Cheng HY. 2011. miRNA-132 orchestrates chromatin re- such as processing bodies (P-bodies) in regulat- modeling and translational control of the circadian clock. ing circadian protein expression has not been Hum Mol Genet 20: 731–751.

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Circadian Posttranscriptional Regulatory Mechanisms in Mammals

Carla B. Green

Cold Spring Harb Perspect Biol published online August 4, 2017

Subject Collection Circadian Rhythms

Circadian Posttranscriptional Regulatory Coordination between Differentially Regulated Mechanisms in Mammals Circadian Clocks Generates Rhythmic Behavior Carla B. Green Deniz Top and Michael W. Young Design Principles of Phosphorylation-Dependent Introduction to Timekeeping in Eukaryotic Circadian Clocks Sandra J. Kuhlman, L. Michon Craig and Jeanne F. Koji L. Ode and Hiroki R. Ueda Duffy Interplay between Microbes and the Circadian Cellular Timekeeping: It's Redox o'Clock Clock Nikolay B. Milev, Sue-Goo Rhee and Akhilesh B. Paola Tognini, Mari Murakami and Paolo Reddy Sassone-Corsi A 50-Year Personal Journey: Location, Gene Molecular Mechanisms of Sleep Homeostasis in Expression, and Circadian Rhythms Flies and Mammals Michael Rosbash Ravi Allada, Chiara Cirelli and Amita Sehgal Regulating the Suprachiasmatic Nucleus (SCN) Membrane Currents, Gene Expression, and Circadian Clockwork: Interplay between Circadian Clocks Cell-Autonomous and Circuit-Level Mechanisms Charles N. Allen, Michael N. Nitabach and Erik D. Herzog, Tracey Hermanstyne, Nicola J. Christopher S. Colwell Smyllie, et al. Systems Chronobiology: Global Analysis of Gene The Plant Circadian Clock: From a Simple Regulation in a 24-Hour Periodic World Timekeeper to a Complex Developmental Manager Jérôme Mermet, Jake Yeung and Felix Naef Sabrina E. Sanchez and Steve A. Kay

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