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A Close Look at Wiggly Chromosomes

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A Close Look at Wiggly Chromosomes Developmental Cell Previews receptor Ptch1. Interestingly, Sanders tem is challenging. To go beyond the Dessaud, E., Yang, L.L., Hill, K., Cox, B., Ulloa, F., et al. (2013) find that tagged Boc and correlative to the mechanistic will require Ribeiro, A., Mynett, A., Novitch, B.G., and Briscoe, J. (2007). Nature 450, 717–720. Cdon localize within filopodia of re- highly specific ways of modifying Shh sponding cells. Furthermore, sustained trafficking processes to exclude filopodia Dierker, T., Dreier, R., Petersen, A., Bordych, C., and Grobe, K. (2009). J. Biol. Chem. 284, 8013– contact is observed between ZPA- while leaving other possible routes of 8022. extended and Cdo/Boc-expressing filo- signal delivery intact. There is also a podia. However, there is no direct need to devise specific ways of modu- Lewis, P.M., Dunn, M.P., McMahon, J.A., Logan, M., Martin, J.F., St-Jacques, B., and McMahon, evidence of a filopodial engagement of lating filopodial dynamics that leave all A.P. (2001). Cell 105, 599–612. Shh by filopodial localized Cdon or other aspects of cell function intact. Boc. As noted above, Shh particles Twenty years following the discovery of Ramı´rez-Weber, F.A., and Kornberg, T.B. (1999). Cell 97, 599–607. actively traffic within filopodia of ZPA Shh, Sanders et al. (2013) uncover a new cells. In contrast, Cdon and Boc are opportunity for fresh insights into the Roy, S., Hsiung, F., and Kornberg, T.B. (2011). reported to occupy fixed positions in workings of a key, vertebrate morphogen. Science 332, 354–358. their filopodia. This raises the question Sanders, T.A., Llagostera, E., and Barna, M. (2013). of how these factors would then traffic REFERENCES Nature, in press. Published online Apr 28, 2013. Shh to Ptch1 in the responding cell. Tukachinsky, H., Kuzmickas, R.P., Jao, C.Y., Liu, The work of Sanders et al. (2013) high- Chamberlain, C.E., Jeong, J., Guo, C., Allen, B.L., and McMahon, A.P. (2008). Development 135, J., and Salic, A. (2012). Cell Reports 2, 308–320. lights the importance of incorporating dy- 1097–1106. namic imaging into what is a largely static Yang, Y., Drossopoulou, G., Chuang, P.T., Duprez, Creanga, A., Glenn, T.D., Mann, R.K., Saunders, D., Marti, E., Bumcrot, D., Vargesson, N., Clarke, framework of amniote development. The A.M., Talbot, W.S., and Beachy, P.A. (2012). Genes J., Niswander, L., McMahon, A., and Tickle, C. data are thought provoking, but the sys- Dev. 26, 1312–1325. (1997). Development 124, 4393–4404. A Close Look at Wiggly Chromosomes Kerry Bloom1,* 1Department of Biology, 623 Fordham Hall CB #3280, University of North Carolina, Chapel Hill, NC 27599-3280, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.devcel.2013.05.005 In a recent issue of Cell, Fisher et al. (2013) use high-resolution time-lapse imaging to peer into bacterial genome (nucleoid) structure. The nucleoid, an elastic filament confined via an internal network, undergoes periodic fluctuations critical in relieving tension. Programmed tethers and their release highlight a primordial mechanical cycle for chromosome segregation. The genome sequence revolution has that is constantly altering its shape. A In a recent issue of Cell, Fisher et al. slowly captured the imagination of the consequence of the constant shape shift- (2013) provide one of the first high-resolu- public, but the genome is much more ing is that, on average, any given gene tion live-imaging series of the bacterial than the ATCGs that made up the DNA may be exposed within the population. genome (known as a nucleoid). The au- polymer. Much remains mysterious about To study how the genome is organized, it thors show that the nucleoid exhibits the behavior of the genome in living cells. is therefore critical to keep cells alive. waves of density changes that propagate First is the DNA packaging problem. For Long polymers such as DNA in a confined from end to end. The implications of these humans, 2 m of DNA must be packed space require a very different solution than findings are startling and provide critical into a 20–30 mm nucleus, and for bacteria, most biologists have been trained to new ways to think about our genetic 2 mm DNA must be packed into a 1 mm study. Rather than worrying about salt makeup as we move away from bucket cell. Second is the accessibility problem. concentration, pH, and osmolarity, we chemistry to take into account physics How can the genome be dramatically need to be concerned with concepts and statistical mechanics. The bacterial compacted yet simultaneously provide such as viscosity, confinement, tethering, genome is not simply stuffed in the cell. huge protein conglomerates such as and thermal noise. Unlike gases, if we Far from being amorphous, there is inter- RNA and DNA polymerase with access to mix two long chain polymers in a confined nal organization to the nucleoid, as specific genes? The genome is far from space, they will segregate simply based evidenced by its helical shape and clear being a static information warehouse. on the penalty incurred (entropic repul- separation from the cell wall. The evi- Rather, it is a mechanically active entity sion) when the two chains collide. dence comes from imaging with a variety 330 Developmental Cell 25, May 28, 2013 ª2013 Elsevier Inc. Developmental Cell Previews of nucleoid labels, such as of supercoils and entangle- fluorescent repressor oper- ments that could prematurely ator system (FROS) (Wiggins stress programmed tethers. et al., 2010), Fis (Hadizadeh The periodic undulations Yazdi et al., 2012), and the act to massage the nucleoid, nucleoid-associated protein thereby relieving tension. HU (Fisher et al., 2013). The This perspective offers new work of Fisher et al. (2013) insight into bacterial chromo- provides direct evidence for some segregation, as well a structure that is longitudi- as cellular mechanisms for nally bundled and radially relieving stress and strain. confined. By using rapid im- Looking beyond the imme- age acquisition, the authors diate dynamics of chromatin find that these bundles are behavior, one of the more pro- dynamic and that waves of found concepts to come from density can be seen to flux the Fisher et al. (2013) study is through the long axis of the the connection of waves (or nucleoid. Polymer confine- cycles) of mechanical undula- ment is generated by an in- tions to early mechanisms of ternal structure that ratchets segregation and cell-cycle down chromatin domains— Figure 1. Brownian Fluctuation of Bead-Spring Polymer Chains regulation. As biologists, we not like stuffing your sleeping Singly tethered polymer chains explore more space relative to doubly tethered are taught to think of building chains. Top: doubly tethered chain; bottom: singly tethered chain. Snapshots bag into its pouch. The in time (left), ensemble behavior over time (right). Model by Paula A. Vasquez, complexity to execute a pro- internal structure observed Department of Mathematics, UNC-Chapel Hill. cess. From the physics, how- here may be analogous to ever, the fidelity of a process protein-based chromosome depends on decreasing scaffolds observed in eukaryotic chro- mechanism to generate heterogeneity complexity and closer adherence to ther- mosomes (Earnshaw et al., 1985) or con- along an otherwise homogeneous poly- modynamics. While DNA-binding pro- straints from protein complexes such as mer chain and is likely to have profound teins that mediate chromatin-skeletal in- condensin and cohesin (Stephens et al., biological implications. Evidence of snaps teractions have evolved from simple 2011) together with DNA entanglements and tethers raises questions about the plasmid-based mechanisms in bacteria (Kawamura et al., 2010). types of cellular tethers (are there to complex kinetochore-based mecha- A key insight from Fisher et al. (2013) programmed tethers like eukaryotic inter- nisms in eukaryotes, there is likely an in- is the consequence of tethering (Fig- phase telomere tethering and nonprog- ternal mechanical cycle conserved be- ure 1). The longitudinal pulses within the rammed or stochastic tethering interac- tween these systems that predates nucleoid correlate with the time and num- tions emerging from entanglements?) these solutions for managing complex ber of what are known as the T1–T4 transi- and how the cell dissolves these attach- DNA polymers during cell division. tions. T1–T4 transitions reflect discrete ments at the appropriate time and place. Is the motion observed by Fisher et al. events toward the completion of replica- The DNA polymer is fundamentally a (2013) completely thermal? We know tion and segregation. The transitions are knotted mess. Replication constantly that chromosomal motion is an energy- abrupt and have been proposed to reflect generates catenates, whereas positive requiring process. The machines that release of tethered sites (Bates and and negative supercoils lead and follow drive chromosome motility—e.g., en- Kleckner, 2005; Joshi et al., 2011). Direct transcription. The local environment of zymes moving along the helix, enzymes visualization of a snapping event provides any given gene in a long-chain polymer breaking and sealing covalent bonds— evidence for rapid elastic recoil of a spe- would be a physicist’s nightmare to do not generate coherent directed cific locus (Fisher et al., 2013). Snapping compute and would take a biologist an motion. Instead of putting heat into the events within confined chromatin poly- eternity to reconstitute. The cell, of system to increase molecular motion, mers have also been observed in cohesin course, has this figured out: the system randomly directed enzymatic activity in- and condensin-rich pericentromeres in thrives on thermal noise. Take a ball of creases the number of conformational budding yeast (Stephens et al., 2013). yarn and let your kitten or granddaughter states (DS, from the Gibbs free energy Tethers emerge as a critical concept in (in my case) mess around for a few hours.
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