- Email: [email protected]
Gene Regulation: Global Transcription Rates Scale with Size
Dispatch R979
understanding of the evolution of cooperation and sociality requires knowledge of how genes and environment interact in shaping the life-history trajectory and social development of individuals.
7.
8.
References 1. Szathmary, E., and Maynard Smith, J. (1995). The major evolutionary transitions. Nature 374, 227–231. 2. Field, J., Paxton, R.J., Soro, A., and Bridge, C. (2010). Cryptic plasticity underlies a major evolutionary transition. Curr. Biol. 20, 2028–2031. 3. Schwarz, M.P., Richards, M.H., and Danforth, B.N. (2007). Changing paradigms in insect social evolution: Insights from halictine and allodapine bees. Annu. Rev. Entomol. 52, 127–150. 4. Danforth, B.N. (2002). Evolution of sociality in a primitively eusocial lineage of bees. Proc. Natl. Acad. Sci. USA 99, 286–290. 5. Eickwort, G.C., Eickwort, J.M., Gordon, J., and Eickwort, M.A. (1996). Solitary behavior in a high altitude population of the social sweat bee Halictus rubicundus (Hymenoptera: Halictidae). Behav. Ecol. Sociobiol. 38, 227–233. 6. Field, J., Shreeves, G., Sumner, S., and Casiraghi, M. (2000). Insurance-based
9.
10.
11.
12.
13.
14.
advantage to helpers in a tropical hover wasp. Nature 404, 869–871. Soro, A., Field, J., Bridge, C., Cardinal, S.C., and Paxton, R.J. (2010). Genetic differentiation across the social transition in a socially polymorphic sweat bee, Halictus rubicundus. Mol. Ecol. 19, 3351–3363. Wcislo, W.T., and Danforth, B.N. (1997). Secondarily solitary: the evolutionary loss of social behavior. Trends Ecol. Evol. 12, 468–474. Ulrich, Y., Perrin, N., and Chapuisat, M. (2009). Flexible social organization and high incidence of drifting in the sweat bee, Halictus scabiosae. Mol. Ecol. 18, 1791–1800. Ratnieks, F.L.W., and Wenseleers, T. (2008). Altruism in insect societies and beyond: voluntary or enforced? Trends Ecol. Evol. 23, 45–52. Ratnieks, F.L.W., Foster, K.R., and Wenseleers, T. (2006). Conflict resolution in insect societies. Annu. Rev. Entomol. 51, 581–608. Keller, L., and Chapuisat, M. (1999). Cooperation among selfish individuals in insect societies. BioScience 49, 899–909. Soucy, S.L., and Danforth, B.N. (2002). Phylogeography of the socially polymorphic sweat bee Halictus rubicundus (Hymenoptera: Halictidae). Evolution 56, 330–341. West-Eberhard, M.J. (1987). Flexible strategy and social evolution. In Animal Societies: Theories and Facts, Y. Itoˆ, J.L. Brown, and
Gene Regulation: Global Transcription Rates Scale with Size Is bigger better? Scientists have long puzzled over the potential relationship between cell size and the rate of mRNA production. A recent report builds a strong case that global transcription rates scale with size. Huzefa Dungrawala1, Arkadi Manukyan2, and Brandt L. Schneider1,* While the size of organisms varies over an almost incomprehensible range, the average size of cells is remarkably invariant between species [1,2]. These observations suggest that cells have an active mechanism to ensure cell size homeostasis. Excessive growth would produce cells of ever increasing size. Conversely, unrestrained proliferation in the absence of adequate growth could result in a mitotic catastrophe. Put simply, cells must have a means of coordinating their rate of cell growth with their rate of division. Collectively, the term ‘cell growth’ refers to the metabolic processes involved in macromolecular anabolism, and the bulk of this consists of DNA, RNA, and protein synthesis. DNA replication occurs only during a discrete phase of the cell cycle. In contrast, protein and RNA synthesis
are continuous processes. While cell proliferation is inarguably exponential, it is considerably less certain if cell growth is exponential. Exponential growth dictates a dependence upon size; large cells grow proportionally faster than small ones. Thus, exponential growth puts a premium on cell size. The potential importance of size has been a hot topic that has teased the minds of philosophers and scientists for hundreds of years. Modern marketers continually batter ‘pop culture’ with the concept that bigger is better. Sometimes the evidence in favor of this idea is inescapable. Strength is nearly always proportional to size, and evidence suggests that longevity and metabolic rates scale with size [1,3]. Large organisms are long-lived, perhaps because they are more metabolically efficient. The average domesticated elephant lives 30–100 times longer than the average laboratory mouse [1]. However,
15.
16.
17.
18.
19.
20.
J. Kikkawa, eds. (Tokyo: Japan Scientific Societies Press), pp. 35–51. Richards, M.H., and Packer, L. (1994). Trophic aspects of caste determination in Halictus ligatus, a primitively eusocial sweat bee. Behav. Ecol. Sociobiol. 34, 385–391. Hirata, M., and Higashi, S. (2008). Degree-day accumulation controlling allopatric and sympatric variations in the sociality of sweat bees, Lasioglossum (Evylaeus) baleicum (Hymenoptera: Halictidae). Behav. Ecol. Sociobiol. 62, 1239–1247. West-Eberhard, M.J. (1989). Phenotypic plasticity and the origins of diversity. Annu. Rev. Ecol. Syst. 20, 249–278. Schwander, T., Lo, N., Beekman, M., Oldroyd, B.P., and Keller, L. (2010). Nature versus nurture in social insect caste differentiation. Trends Ecol. Evol. 25, 275–282. West-Eberhard, M.J. (2003). Developmental Plasticity and Evolution, (New York: Oxford University Press). Nedelcu, A.M. (2009). Environmentally induced responses co-opted for reproductive altruism. Biol. Lett. 5, 805–808.
Department of Ecology and Evolution, University of Lausanne, Biophore, Quartier Sorge, CH-1015 Lausanne, Switzerland. E-mail: [email protected] DOI: 10.1016/j.cub.2010.10.033
considerably less is known about the relationship between size and basic cellular processes like RNA production. For example, as cells enlarge, their DNA to protein ratio declines (Figure 1). Thus, with respect to their mass, the relative gene dosage of each cell decreases. Does this result in a concomitant decrease (or increase?) in global transcription rates? In this issue of Current Biology, Zhurinsky et al. [4] re-examine the relationship between the rate of mRNA synthesis and cell size. With respect to global mRNA production, two very general processes occur with cell cycle progression. First, in order to produce nearly identically sized daughters, cells continually increase in size as they advance towards cytokinesis. Second, cells replicate their DNA during S-phase. What remains to be resolved is how each of these events affects global RNA transcription. Initial experiments conducted in synchronized yeast cultures suggested that mRNA transcription rates abruptly doubled after DNA replication [5,6]. Similar results were obtained in HeLa or CH-Don-C cells [7–9]. Since the sharp rate change for mRNA production was not mirrored by the rate at which cells increased in size, these data were more consistent with a gene
Relative rate
Current Biology Vol 20 No 22 R980
Transcription rate Transcription rate per unit protein
Cell size DNA to protein ratio Current Biology
Figure 1. A relationship between global mRNA transcription rates and cell size? By comparing small size mutants to large cell mutants, the average cell size of asynchronous cultures can increase 3–5 fold. However, since DNA content remains relatively unchanged on a per cell basis, the DNA to protein ratio increases as size decreases. Using this genetic approach, Zhurinsky et al. [4] have demonstrated that the rate of global transcription scales with size (solid black line) and is directly proportional to the protein content per cell (solid gray line). DNA to protein ratios (or gene dosages) only become limiting for transcription in very large cells (dashed line).
dosage model. This interpretation was also supported by the finding that halting DNA replication via hydroxyurea treatments concomitantly decreased mRNA production rates [5]. Taken together, these results suggested that mRNA transcription rates correlated more closely with gene copy number than with cell size. However, there is also considerable evidence suggesting that the rate of RNA transcription increases continuously throughout the cell cycle in a pattern that correlates strongly with cell size. For example, uridine pulse-labeling experiments of human and mouse cells provided evidence for exponential (aka size-dependent) increases in RNA synthesis [10,11]. Size-dependent exponential increases in RNA synthesis have also been observed in budding and fission yeast [12–14]. In addition, several different studies have shown that cellular RNA contents closely mirror cell size and total protein content even in cells with high DNA to protein ratios [12,13,15]. Thus, the issue of how gene dosage affects RNA synthesis, and whether global transcription rates scale with size, has remained largely unresolved. To examine these questions in more depth and with modern genomic technologies, Zhurinsky et al. [4] have compared the total RNA production
rate in a small size mutant, wee1-50, to a large size mutant, cdc25-22. Since some of the discrepancies reported above might be due to artifacts associated with cell cycle synchronization, asynchronous cultures were used. In so doing, they report that global RNA transcription rates closely mirrored cell size. Specifically, they found that the ratio of total RNA to protein was constant. By using microarray analyses to compare the differential expression of 4,655 genes between small and large cells, it was found that w98% of these genes were equivalently regulated [4]. In addition, chromatin immunoprecipitation (ChIP) assays revealed that the level of promoter occupancy by RNA polymerase II also strongly scaled with size. Indeed, only 1.8% of the 4638 genes showed significant deviation from the median values. Even more telling, only 18 genes (w0.4%) were differentially regulated in both the mRNA microarray and ChIP experiments [4]. These results demonstrate that within a two-fold size range, global transcription rates appear to be size-dependent. Using strains with temperaturesensitive mutations to produce greatly enlarged cells, Zhurinsky et al. [4] showed that total RNA synthesis rates increased even in very large cells. Microarray analyses again revealed that the transcription rate of individual genes generally increased in direct proportion to size. However, after a 4–5 fold increase in size, the total transcription rate began to level off (Figure 1). Significantly, the rate of protein synthesis also leveled off at this same time. These results suggested that only at very large sizes does ‘gene dosage’ become limiting for transcription rates. However, in large cell mutants in which DNA replication is not blocked, global transcription rates continuously increased as cells enlarged. Put simply, these results suggest that global transcription rates scale with size. During balanced cell growth, in order to maintain homeostasis, individual cells must double their cell mass each generation. While the genetic and molecular pathways that govern this process are being elucidated [2,16,17], the basic mathematical pattern that governs simple biological processes, like the rate of RNA synthesis throughout the cell cycle, has remained
controversial. Using a number of clever approaches, Zhurinsky et al. [4] demonstrate that the expression level of >98% of all genes in fission yeast are tightly coordinated over a wide range of cell sizes. Since even under physiological conditions individual cells can have nearly a five-fold range of sizes, these results suggest the existence of a compensatory mechanism that couples global transcription rates to size. While this type of global control provides a metabolically efficient mechanism for modulating cell growth, the molecular mechanisms whereby this is achieved remain relatively unknown. Moreover, despite this advancement, there is a great deal more to be learned about the relationship between size and transcriptional control. For example, nutrient limiting conditions profoundly disrupt the coordination between size and gene expression [18,19]. However, the implications of these observations with respect to Zhurinsky et al.’s [4] findings are unclear at this point. In addition, the transcription of a number of cell cycle regulated genes in budding yeast does not scale smoothly with size [20]. For example, the expression of the G1-phase cyclins, CLN1 and CLN2, abruptly switches from ‘off’ to ‘maximal’ within a very small size range [20]. Nonetheless, Zhurinsky et al. [4] have demonstrated that melding classic genetics with modern genomics can shed light into the dark recesses of simple, but long-standing biological questions.
References 1. Bonner, J.T. (2006). Why Size Matters: From Bacteria to Blue Whales (Princeton: Princeton University Press). 2. Jorgensen, P., and Tyers, M. (2004). How cells coordinate growth and division. Curr. Biol. 14, R1014–R1027. 3. West, G.B., and Brown, J.H. (2005). The origin of allometric scaling laws in biology from genomes to ecosystems: towards a quantitative unifying theory of biological structure and organization. J. Exp. Biol. 208, 1575–1592. 4. Zhurinsky, J., Leonhard, K., Watt, S., Marguerat, S., Bahler, J., and Nurse, P. (2010). A coordinated global control over cellular transcription. Curr. Biol. 20, 2010–2015. 5. Fraser, R.S., and Moreno, F. (1976). Rates of synthesis of polyadenylated messenger RNA and ribosomal RNA during the cell cycle of Schizosaccharomyces pombe. With an appendix: calculation of the pattern of protein accumulation from observed changes in the rate of messenger RNA synthesis. J. Cell Sci. 21, 497–521. 6. Fraser, R.S., and Carter, B.L. (1976). Synthesis of polyadenylated messenger RNA during the cell cycle of Saccharomyces cerevisiae. J. Mol. Biol. 104, 223–242.
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7. Mitchison, J.M. (2003). Growth during the cell cycle. Int. Rev. Cytol. 226, 165–258. 8. Pfeiffer, S.E. (1968). RNA synthesis in synchronously growing populations of HeLa S3 cells. II. Rate of synthesis of individual RNA fractions. J. Cell. Physiol. 71, 95–104. 9. Stubblefield, E., Klevecz, R., and Deaven, L. (1967). Synchronized mammalian cell cultures. I. Cell replication cycle and macromolecular synthesis following brief colcemid arrest of mitosis. J. Cell. Physiol. 69, 345–353. 10. Scharff, M.D., and Robbins, E. (1965). Synthesis of ribosomal RNA in synchronized HeLa cells. Nature 208, 464–466. 11. Terasima, T., and Tolmach, L.J. (1963). Growth and nucleic acid synthesis in synchronously dividing populations of HeLa cells. Exp. Cell Res. 30, 344–362. 12. Fraser, R.S., and Nurse, P. (1978). Novel cell cycle control of RNA synthesis in yeast. Nature 271, 726–730. 13. Fraser, R.S., and Nurse, P. (1979). Altered patterns of ribonucleic acid synthesis during the cell cycle: a mechanism compensating for variation in gene concentration. J. Cell Sci. 35, 25–40. 14. Elliott, S.G., and McLaughlin, C.S. (1983). The yeast cell cycle: coordination of growth and
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division rates. Prog. Nucl. Acid Res. Mol. Biol. 28, 143–176. Schmidt, E.E., and Schibler, U. (1995). Cell size regulation, a mechanism that controls cellular RNA accumulation: consequences on regulation of the ubiquitous transcription factors Oct1 and NF-Y and the liver-enriched transcription factor DBP. J. Cell Biol. 128, 467–483. Jorgensen, P., Nishikawa, J.L., Breitkreutz, B.J., and Tyers, M. (2002). Systematic identification of pathways that couple cell growth and division in yeast. Science 297, 395–400. Zhang, J., Schneider, C., Ottmers, L., Rodriguez, R., Day, A., Markwardt, J., and Schneider, B.L. (2002). Genomic scale mutant hunt identifies cell size homeostasis genes in S. cerevisiae. Curr. Biol. 12, 1992–2001. Regenberg, B., Grotkjaer, T., Winther, O., Fausboll, A., Akesson, M., Bro, C., Hansen, L.K., Brunak, S., and Nielsen, J. (2006). Growth-rate regulated genes have profound impact on interpretation of transcriptome profiling in Saccharomyces cerevisiae. Genome Biol. 7, R107.
Life History: The Energy-Efficient Orangutan A study of orangutans’ daily energy expenditure confirmed exceptionally slow metabolism. It suggests they evolved a lifestyle designed to minimize energy use. If so, shifting to a higher energy-use strategy may help explain how humans evolved. Anne E. Russon The pattern Aesop mused upon in the 5th century BCE, that animals can differ in their pace of life — tortoises being slow, hares being fast — has become one of the most important topics in modern evolutionary biology. In biology, the pace of a species’ life cycle from conception to death is called its ‘life history’. It is defined by the timing of events in an individual’s life that are critical to survival and reproduction, e.g., longevity, age at first reproduction, gestation length, the interval between births and age at weaning [1]. Life histories reflect packages of linked traits that vary the overall pace of life from slow to fast: slow livers tend to be large, long lived, and produce few offspring, whereas fast livers tend be small, die young, and reproduce more. The big evolutionary question is: why are there different life histories? A new study by Pontzer and colleagues [2] brings orangutans to front stage in the study of life history evolution. Orangutans are well known for slow pace of life (Figure 1) — the
slowest of all the great apes. But because of that, they were the neglected apes of the 20th century, dismissed as sluggish, slothful and uninteresting. They have the latest age of first reproduction (over 15 years), longest intervals between births (7-9 years) and latest age at weaning (6-10 years) [3]. They also travel little, and do so slowly; they socialize little and rest a lot. Pontzer’s work [2] now offers new evidence about the basis for their exceptionally slow life histories. Generally, it appears that species’ life histories have evolved to balance diverse selection pressures. For this reason, they are often called ‘strategies’. For instance, they reflect the effects of major environmental challenges on mortality during adulthood (the reproductive period); species with lower adult mortality rates tend to have slower life histories [4]. Orangutan slowness is consistent with the poor and fickle food supply of Southeast Asian forests: during the worst food lows, they may survive on bark and their own fat stores for months on end [5]. Other traits are also
19. Brauer, M.J., Huttenhower, C., Airoldi, E.M., Rosenstein, R., Matese, J.C., Gresham, D., Boer, V.M., Troyanskaya, O.G., and Botstein, D. (2008). Coordination of growth rate, cell cycle, stress response, and metabolic activity in yeast. Mol. Biol. Cell 19, 352–367. 20. Spellman, P.T., Sherlock, G., Zhang, M.Q., Iyer, V.R., Anders, K., Eisen, M.B., Brown, P.O., Botstein, D., and Futcher, B. (1998). Comprehensive identification of cell cycleregulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization. Mol. Biol. Cell 9, 3273–3297.
1Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA. 2Institute of Molecular Biology, National Academy of Sciences of Armenia, Yerevan, Armenia. *E-mail: [email protected]
DOI: 10.1016/j.cub.2010.09.064
tied to a species’ life history: notably, large body size and large brain size correlate with slow life history. A common view is that these links are due to tradeoffs in allocating energy to survival as opposed to reproduction [6]. In great apes, for instance, growth and juvenile development may be delayed or in humans gut size may be reduced, to pay the costs of growing or operating these species’ large brains [7,8]. Pontzer’s group [2] explored newer views that different life history strategies reflect different management of total energy use — intake and expenditure, or throughput, not just different energy allocation. Focusing on energy use emphasizes the interactions within the set of interrelated ecological, behavioral and physiological traits that characterize the species, that is, the species’ ‘lifestyle’ [9]. Strategies for energy use seem to vary from high to low, depending on food availability and mortality threats [9–12]: abundant and reliable food supplies favor high energy-use strategies, while unpredictable food supplies or high predation risks while foraging favor low energy-use strategies. Importantly, species with access to abundant, reliable food resources may be able to reproduce more than those whose food resources are low in abundance, unreliable, or dangerous to obtain [12]. If physiology is a key factor in energy use, then metabolism must play an important role [13].
understanding of the evolution of cooperation and sociality requires knowledge of how genes and environment interact in shaping the life-history trajectory and social development of individuals.
7.
8.
References 1. Szathmary, E., and Maynard Smith, J. (1995). The major evolutionary transitions. Nature 374, 227–231. 2. Field, J., Paxton, R.J., Soro, A., and Bridge, C. (2010). Cryptic plasticity underlies a major evolutionary transition. Curr. Biol. 20, 2028–2031. 3. Schwarz, M.P., Richards, M.H., and Danforth, B.N. (2007). Changing paradigms in insect social evolution: Insights from halictine and allodapine bees. Annu. Rev. Entomol. 52, 127–150. 4. Danforth, B.N. (2002). Evolution of sociality in a primitively eusocial lineage of bees. Proc. Natl. Acad. Sci. USA 99, 286–290. 5. Eickwort, G.C., Eickwort, J.M., Gordon, J., and Eickwort, M.A. (1996). Solitary behavior in a high altitude population of the social sweat bee Halictus rubicundus (Hymenoptera: Halictidae). Behav. Ecol. Sociobiol. 38, 227–233. 6. Field, J., Shreeves, G., Sumner, S., and Casiraghi, M. (2000). Insurance-based
9.
10.
11.
12.
13.
14.
advantage to helpers in a tropical hover wasp. Nature 404, 869–871. Soro, A., Field, J., Bridge, C., Cardinal, S.C., and Paxton, R.J. (2010). Genetic differentiation across the social transition in a socially polymorphic sweat bee, Halictus rubicundus. Mol. Ecol. 19, 3351–3363. Wcislo, W.T., and Danforth, B.N. (1997). Secondarily solitary: the evolutionary loss of social behavior. Trends Ecol. Evol. 12, 468–474. Ulrich, Y., Perrin, N., and Chapuisat, M. (2009). Flexible social organization and high incidence of drifting in the sweat bee, Halictus scabiosae. Mol. Ecol. 18, 1791–1800. Ratnieks, F.L.W., and Wenseleers, T. (2008). Altruism in insect societies and beyond: voluntary or enforced? Trends Ecol. Evol. 23, 45–52. Ratnieks, F.L.W., Foster, K.R., and Wenseleers, T. (2006). Conflict resolution in insect societies. Annu. Rev. Entomol. 51, 581–608. Keller, L., and Chapuisat, M. (1999). Cooperation among selfish individuals in insect societies. BioScience 49, 899–909. Soucy, S.L., and Danforth, B.N. (2002). Phylogeography of the socially polymorphic sweat bee Halictus rubicundus (Hymenoptera: Halictidae). Evolution 56, 330–341. West-Eberhard, M.J. (1987). Flexible strategy and social evolution. In Animal Societies: Theories and Facts, Y. Itoˆ, J.L. Brown, and
Gene Regulation: Global Transcription Rates Scale with Size Is bigger better? Scientists have long puzzled over the potential relationship between cell size and the rate of mRNA production. A recent report builds a strong case that global transcription rates scale with size. Huzefa Dungrawala1, Arkadi Manukyan2, and Brandt L. Schneider1,* While the size of organisms varies over an almost incomprehensible range, the average size of cells is remarkably invariant between species [1,2]. These observations suggest that cells have an active mechanism to ensure cell size homeostasis. Excessive growth would produce cells of ever increasing size. Conversely, unrestrained proliferation in the absence of adequate growth could result in a mitotic catastrophe. Put simply, cells must have a means of coordinating their rate of cell growth with their rate of division. Collectively, the term ‘cell growth’ refers to the metabolic processes involved in macromolecular anabolism, and the bulk of this consists of DNA, RNA, and protein synthesis. DNA replication occurs only during a discrete phase of the cell cycle. In contrast, protein and RNA synthesis
are continuous processes. While cell proliferation is inarguably exponential, it is considerably less certain if cell growth is exponential. Exponential growth dictates a dependence upon size; large cells grow proportionally faster than small ones. Thus, exponential growth puts a premium on cell size. The potential importance of size has been a hot topic that has teased the minds of philosophers and scientists for hundreds of years. Modern marketers continually batter ‘pop culture’ with the concept that bigger is better. Sometimes the evidence in favor of this idea is inescapable. Strength is nearly always proportional to size, and evidence suggests that longevity and metabolic rates scale with size [1,3]. Large organisms are long-lived, perhaps because they are more metabolically efficient. The average domesticated elephant lives 30–100 times longer than the average laboratory mouse [1]. However,
15.
16.
17.
18.
19.
20.
J. Kikkawa, eds. (Tokyo: Japan Scientific Societies Press), pp. 35–51. Richards, M.H., and Packer, L. (1994). Trophic aspects of caste determination in Halictus ligatus, a primitively eusocial sweat bee. Behav. Ecol. Sociobiol. 34, 385–391. Hirata, M., and Higashi, S. (2008). Degree-day accumulation controlling allopatric and sympatric variations in the sociality of sweat bees, Lasioglossum (Evylaeus) baleicum (Hymenoptera: Halictidae). Behav. Ecol. Sociobiol. 62, 1239–1247. West-Eberhard, M.J. (1989). Phenotypic plasticity and the origins of diversity. Annu. Rev. Ecol. Syst. 20, 249–278. Schwander, T., Lo, N., Beekman, M., Oldroyd, B.P., and Keller, L. (2010). Nature versus nurture in social insect caste differentiation. Trends Ecol. Evol. 25, 275–282. West-Eberhard, M.J. (2003). Developmental Plasticity and Evolution, (New York: Oxford University Press). Nedelcu, A.M. (2009). Environmentally induced responses co-opted for reproductive altruism. Biol. Lett. 5, 805–808.
Department of Ecology and Evolution, University of Lausanne, Biophore, Quartier Sorge, CH-1015 Lausanne, Switzerland. E-mail: [email protected] DOI: 10.1016/j.cub.2010.10.033
considerably less is known about the relationship between size and basic cellular processes like RNA production. For example, as cells enlarge, their DNA to protein ratio declines (Figure 1). Thus, with respect to their mass, the relative gene dosage of each cell decreases. Does this result in a concomitant decrease (or increase?) in global transcription rates? In this issue of Current Biology, Zhurinsky et al. [4] re-examine the relationship between the rate of mRNA synthesis and cell size. With respect to global mRNA production, two very general processes occur with cell cycle progression. First, in order to produce nearly identically sized daughters, cells continually increase in size as they advance towards cytokinesis. Second, cells replicate their DNA during S-phase. What remains to be resolved is how each of these events affects global RNA transcription. Initial experiments conducted in synchronized yeast cultures suggested that mRNA transcription rates abruptly doubled after DNA replication [5,6]. Similar results were obtained in HeLa or CH-Don-C cells [7–9]. Since the sharp rate change for mRNA production was not mirrored by the rate at which cells increased in size, these data were more consistent with a gene
Relative rate
Current Biology Vol 20 No 22 R980
Transcription rate Transcription rate per unit protein
Cell size DNA to protein ratio Current Biology
Figure 1. A relationship between global mRNA transcription rates and cell size? By comparing small size mutants to large cell mutants, the average cell size of asynchronous cultures can increase 3–5 fold. However, since DNA content remains relatively unchanged on a per cell basis, the DNA to protein ratio increases as size decreases. Using this genetic approach, Zhurinsky et al. [4] have demonstrated that the rate of global transcription scales with size (solid black line) and is directly proportional to the protein content per cell (solid gray line). DNA to protein ratios (or gene dosages) only become limiting for transcription in very large cells (dashed line).
dosage model. This interpretation was also supported by the finding that halting DNA replication via hydroxyurea treatments concomitantly decreased mRNA production rates [5]. Taken together, these results suggested that mRNA transcription rates correlated more closely with gene copy number than with cell size. However, there is also considerable evidence suggesting that the rate of RNA transcription increases continuously throughout the cell cycle in a pattern that correlates strongly with cell size. For example, uridine pulse-labeling experiments of human and mouse cells provided evidence for exponential (aka size-dependent) increases in RNA synthesis [10,11]. Size-dependent exponential increases in RNA synthesis have also been observed in budding and fission yeast [12–14]. In addition, several different studies have shown that cellular RNA contents closely mirror cell size and total protein content even in cells with high DNA to protein ratios [12,13,15]. Thus, the issue of how gene dosage affects RNA synthesis, and whether global transcription rates scale with size, has remained largely unresolved. To examine these questions in more depth and with modern genomic technologies, Zhurinsky et al. [4] have compared the total RNA production
rate in a small size mutant, wee1-50, to a large size mutant, cdc25-22. Since some of the discrepancies reported above might be due to artifacts associated with cell cycle synchronization, asynchronous cultures were used. In so doing, they report that global RNA transcription rates closely mirrored cell size. Specifically, they found that the ratio of total RNA to protein was constant. By using microarray analyses to compare the differential expression of 4,655 genes between small and large cells, it was found that w98% of these genes were equivalently regulated [4]. In addition, chromatin immunoprecipitation (ChIP) assays revealed that the level of promoter occupancy by RNA polymerase II also strongly scaled with size. Indeed, only 1.8% of the 4638 genes showed significant deviation from the median values. Even more telling, only 18 genes (w0.4%) were differentially regulated in both the mRNA microarray and ChIP experiments [4]. These results demonstrate that within a two-fold size range, global transcription rates appear to be size-dependent. Using strains with temperaturesensitive mutations to produce greatly enlarged cells, Zhurinsky et al. [4] showed that total RNA synthesis rates increased even in very large cells. Microarray analyses again revealed that the transcription rate of individual genes generally increased in direct proportion to size. However, after a 4–5 fold increase in size, the total transcription rate began to level off (Figure 1). Significantly, the rate of protein synthesis also leveled off at this same time. These results suggested that only at very large sizes does ‘gene dosage’ become limiting for transcription rates. However, in large cell mutants in which DNA replication is not blocked, global transcription rates continuously increased as cells enlarged. Put simply, these results suggest that global transcription rates scale with size. During balanced cell growth, in order to maintain homeostasis, individual cells must double their cell mass each generation. While the genetic and molecular pathways that govern this process are being elucidated [2,16,17], the basic mathematical pattern that governs simple biological processes, like the rate of RNA synthesis throughout the cell cycle, has remained
controversial. Using a number of clever approaches, Zhurinsky et al. [4] demonstrate that the expression level of >98% of all genes in fission yeast are tightly coordinated over a wide range of cell sizes. Since even under physiological conditions individual cells can have nearly a five-fold range of sizes, these results suggest the existence of a compensatory mechanism that couples global transcription rates to size. While this type of global control provides a metabolically efficient mechanism for modulating cell growth, the molecular mechanisms whereby this is achieved remain relatively unknown. Moreover, despite this advancement, there is a great deal more to be learned about the relationship between size and transcriptional control. For example, nutrient limiting conditions profoundly disrupt the coordination between size and gene expression [18,19]. However, the implications of these observations with respect to Zhurinsky et al.’s [4] findings are unclear at this point. In addition, the transcription of a number of cell cycle regulated genes in budding yeast does not scale smoothly with size [20]. For example, the expression of the G1-phase cyclins, CLN1 and CLN2, abruptly switches from ‘off’ to ‘maximal’ within a very small size range [20]. Nonetheless, Zhurinsky et al. [4] have demonstrated that melding classic genetics with modern genomics can shed light into the dark recesses of simple, but long-standing biological questions.
References 1. Bonner, J.T. (2006). Why Size Matters: From Bacteria to Blue Whales (Princeton: Princeton University Press). 2. Jorgensen, P., and Tyers, M. (2004). How cells coordinate growth and division. Curr. Biol. 14, R1014–R1027. 3. West, G.B., and Brown, J.H. (2005). The origin of allometric scaling laws in biology from genomes to ecosystems: towards a quantitative unifying theory of biological structure and organization. J. Exp. Biol. 208, 1575–1592. 4. Zhurinsky, J., Leonhard, K., Watt, S., Marguerat, S., Bahler, J., and Nurse, P. (2010). A coordinated global control over cellular transcription. Curr. Biol. 20, 2010–2015. 5. Fraser, R.S., and Moreno, F. (1976). Rates of synthesis of polyadenylated messenger RNA and ribosomal RNA during the cell cycle of Schizosaccharomyces pombe. With an appendix: calculation of the pattern of protein accumulation from observed changes in the rate of messenger RNA synthesis. J. Cell Sci. 21, 497–521. 6. Fraser, R.S., and Carter, B.L. (1976). Synthesis of polyadenylated messenger RNA during the cell cycle of Saccharomyces cerevisiae. J. Mol. Biol. 104, 223–242.
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Life History: The Energy-Efficient Orangutan A study of orangutans’ daily energy expenditure confirmed exceptionally slow metabolism. It suggests they evolved a lifestyle designed to minimize energy use. If so, shifting to a higher energy-use strategy may help explain how humans evolved. Anne E. Russon The pattern Aesop mused upon in the 5th century BCE, that animals can differ in their pace of life — tortoises being slow, hares being fast — has become one of the most important topics in modern evolutionary biology. In biology, the pace of a species’ life cycle from conception to death is called its ‘life history’. It is defined by the timing of events in an individual’s life that are critical to survival and reproduction, e.g., longevity, age at first reproduction, gestation length, the interval between births and age at weaning [1]. Life histories reflect packages of linked traits that vary the overall pace of life from slow to fast: slow livers tend to be large, long lived, and produce few offspring, whereas fast livers tend be small, die young, and reproduce more. The big evolutionary question is: why are there different life histories? A new study by Pontzer and colleagues [2] brings orangutans to front stage in the study of life history evolution. Orangutans are well known for slow pace of life (Figure 1) — the
slowest of all the great apes. But because of that, they were the neglected apes of the 20th century, dismissed as sluggish, slothful and uninteresting. They have the latest age of first reproduction (over 15 years), longest intervals between births (7-9 years) and latest age at weaning (6-10 years) [3]. They also travel little, and do so slowly; they socialize little and rest a lot. Pontzer’s work [2] now offers new evidence about the basis for their exceptionally slow life histories. Generally, it appears that species’ life histories have evolved to balance diverse selection pressures. For this reason, they are often called ‘strategies’. For instance, they reflect the effects of major environmental challenges on mortality during adulthood (the reproductive period); species with lower adult mortality rates tend to have slower life histories [4]. Orangutan slowness is consistent with the poor and fickle food supply of Southeast Asian forests: during the worst food lows, they may survive on bark and their own fat stores for months on end [5]. Other traits are also
19. Brauer, M.J., Huttenhower, C., Airoldi, E.M., Rosenstein, R., Matese, J.C., Gresham, D., Boer, V.M., Troyanskaya, O.G., and Botstein, D. (2008). Coordination of growth rate, cell cycle, stress response, and metabolic activity in yeast. Mol. Biol. Cell 19, 352–367. 20. Spellman, P.T., Sherlock, G., Zhang, M.Q., Iyer, V.R., Anders, K., Eisen, M.B., Brown, P.O., Botstein, D., and Futcher, B. (1998). Comprehensive identification of cell cycleregulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization. Mol. Biol. Cell 9, 3273–3297.
1Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA. 2Institute of Molecular Biology, National Academy of Sciences of Armenia, Yerevan, Armenia. *E-mail: [email protected]
DOI: 10.1016/j.cub.2010.09.064
tied to a species’ life history: notably, large body size and large brain size correlate with slow life history. A common view is that these links are due to tradeoffs in allocating energy to survival as opposed to reproduction [6]. In great apes, for instance, growth and juvenile development may be delayed or in humans gut size may be reduced, to pay the costs of growing or operating these species’ large brains [7,8]. Pontzer’s group [2] explored newer views that different life history strategies reflect different management of total energy use — intake and expenditure, or throughput, not just different energy allocation. Focusing on energy use emphasizes the interactions within the set of interrelated ecological, behavioral and physiological traits that characterize the species, that is, the species’ ‘lifestyle’ [9]. Strategies for energy use seem to vary from high to low, depending on food availability and mortality threats [9–12]: abundant and reliable food supplies favor high energy-use strategies, while unpredictable food supplies or high predation risks while foraging favor low energy-use strategies. Importantly, species with access to abundant, reliable food resources may be able to reproduce more than those whose food resources are low in abundance, unreliable, or dangerous to obtain [12]. If physiology is a key factor in energy use, then metabolism must play an important role [13].