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Abstract: Mitotic chromosomes are among the most recognizable structures in the cell, yet for over a century their internal organization remains largely unsolved. We applied chromosome conformation capture methods, 5C and Hi-C, across the cell cycle and revealed two distinct three-dimensional folding states of the human genome. We show that the highly compartmentalized and cell type specific organization described previously for nonsynchronous cells is restricted to interphase. In metaphase, we identified a homogenous folding state that is locus-independent, common to all chromosomes, and consistent among cell types, suggesting a general principle of metaphase chromosome organization. Using polymer simulations, we found that metaphase Hi-C data are inconsistent with classic hierarchical models and are instead best described by a linearly organized longitudinally compressed array of consecutive chromatin loops.
High-Resolution Figures from the Main Text: Main Figures
Supplemental Material with High-Resolution Figures: Supplemental Figures
Movie M1. Organization of 10Mb layers in linear organization and cylindrical geometry model (Fig4a). Two 10Mb layers are highlighted in red and blue in the same conformation, with different sizes of a separating region (shown in thin grey as the rest of the chain). Separation from left to right: 0Mb, 5Mb, and 10Mb. Adjacent 10Mb layers are highly intermingled, whereas layers separated by 10Mb rarely intermingle.
Movie M2. Loops-on-the-scaffold model (Fig. 4c) with 14 loops highlighted. 14 highlighted loops are equally spaced by 48 loops (on average 4Mb); each loop is shown in its own color, changing from blue to red along the length of the chromosome. Six monomers at the base of each loop are shown in non-transparent brown; bases of the loops form a scaffold in the center of the chromosome. The rest of the polymer is shown in transparent grey.
Movie M3. Loops-on-the-scaffold model (Fig. 4c) with 50 consecutive loops highlighted (~ 4Mb). Variant of Movie M2. Color of the loops changes from blue to red along the length of the highlighted chromosome region.
Movie M4. Organization of 10Mb layers in the loops on the scaffold model (Fig. 4c). A conformation from the loops-on-the-scaffold model, as in Movie M1. Six monomers at each loop base are colored in brown, and covered by a brown surface shell to increase visibility of the central scaffold. Actual arrangement of the loop bases in this model can be seen in movies M2 and M3.
Movie M5. Two-step process of mitotic chromosome folding (Fig. 5). Four monomers at the base of each loop (i.e. two monomers on each side) are shown in brown. Note, that the process of loop extrusion by SMC complexes was not explicitly modeled.
Movie M6. Two-step process of mitotic chromosome folding with highlighted loops (Fig. 5). 14 loops, each separated by 20 intervening loops, are highlighted.
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