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Genome organization during the cell cycle: unity in division

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During the cell cycle, the genome must undergo dramatic changes in structure, from a decondensed, yet highly organized interphase structure to a condensed, generic mitotic chromosome and then back again. For faithful cell division, the genome must be replicated and chromosomes and sister chromatids physically segregated from one another. Throughout these processes, there is feedback and tension between the information‐storing role and the physical properties of chromosomes. With a combination of recent techniques in fluorescence microscopy, chromosome conformation capture (Hi‐C), biophysical experiments, and computational modeling, we can now attribute mechanisms to many long‐observed features of chromosome structure changes during cell division. Apparent conflicts that arise when integrating the concepts from these different proposed mechanisms emphasize that orchestrating chromosome organization during cell division requires a complex system of factors rather than a simple pathway. Cell division is both essential for and threatening to proper genome organization. As interphase three‐dimensional (3D) genome structure is quite static at a global level, cell division provides an important window of opportunity to make substantial changes in 3D genome organization in daughter cells, allowing for proper differentiation and development. Mistakes in the process of chromosome condensation or rebuilding the structure after mitosis can lead to diseases such as cancer, premature aging, and neurodegeneration. WIREs Syst Biol Med 2017, 9:e1389. doi: 10.1002/wsbm.1389 This article is categorized under: Laboratory Methods and Technologies > Genetic/Genomic Methods Laboratory Methods and Technologies > Imaging Biological Mechanisms > Regulatory Biology
(a) Historic observations of stained banding patterns on mitotic chromosomes (left; Reprinted with permission from Ref 51. Copyright 1983 Springer International Publishing) are explained by recently observed alternating patterns of active histone marks (H3K4me2) and inactive former lamin associating domains (LADs) (right; Reprinted with permission from Ref 25. Copyright 2013 Cell Press). (b) Recent computational simulations of loop extrusion by cohesin produce chromosomes with loops along a scaffold (right) reminiscent of those revealed by electron microscopy (EM) after histone depletion in 1977 (left; Reprinted with permission from Ref 47. Copyright 1977 Cell Press). (c) Similar computational simulations of loop extrustion (right) can produce a whole mitotic chromosome structure remarkably similar to the ultrastructure revealed by pseudo‐3D EM in 1974 (left; Reprinted with permission from Ref 53. Copyright 1974 Springer International Publishing). Permission obtained for figure panel reuse. Loop‐extrusion model reprinted with permission from Ref. 52. Copyright Creative Commons Attribution License. https://creativecommons.org/licenses/by/4.0/.
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Potential stability of TADs during replication. (a) Compartment identity defines replication timing boundaries. TADs (numbered circles) located in the A compartment (red) replicate earlier than those located in the B compartment (blue), so the TAD boundary between TAD 6 and 7 is both a compartment and a replication timing boundary (green line). As cells differentiate, TADs often switch compartments, which in turn changes their replication timing to match their new compartments. Now the boundaries of TAD 4 become both compartment and timing boundaries. (b) A potential model by which TADs could unfold sequentially while maintaining their boundaries during replication. Note that TADs are drawn only schematically to illustrate the potential decondensation within TAD boundaries, and this schematic is not intended to portray mechanisms of TAD formation. Green circles represent the replication machinery.
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Interphase 3D genome organization from single nucleosomes to chromosome territories. (Reprinted with permission from Ref . Copyright 2015 Available under a Creative Commons Attribution License. https://creativecommons.org/licenses/by/4.0/)
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Current proposed models explain chromosome compaction during cell division. The loop‐extrusion model (left) proposes a progressive compaction of chromatin that can be explained by the action of loop‐extrusion factors like cohesin. The stress cycle model (right) also uses this idea, but proposes that an intermediate step, which includes cycles of tether/energy release and further compaction, are needed before the final structure is produced. Both models propose that mutually repelling radially organized loops along a compacted central axis form the final mitotic chromosome.
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