Mitotic Chromosomes as Mechanical Objects
Expansion/Compaction Stress Cycles. We have discovered that chromosomal events are driven by global chromatin compaction/expansion cycles that correspond to cycles of accumulation and release of mechanical stress. These cycles operate in parallel linkage to the cell cycle engine (Kleckner et al., 2004; Liang et al., 2015).
Structural Bridges between Sister Chromatids We have identified a new basic feature of mitotic chromosomes: split sister chromatid axes are linked by DNA/structure bridges from late prophase to anaphase. These bridges are structurally robust, in accord with roles in shepherding chromosomes through the turblence of chromosome compaction, spindle formation and anaphase separation. The existence of bridges also challenges current dogma that metaphase chromosomes are helically coiled (Chu et al., submitted).
Mechanically-promoted One-dimensional Spatial Patterning. Bridges between sister chromatids (above)s are evenly spaced, implying that bridge emergence represents a case of spatial patterning along/within/among chromosomes. We find that bridges emerge by a two-tiered mechanical process in which axial torsional stress plays a promienent role (Chu et al., submitted). These findings directly link an important chromosomal process to the classical theories for elastic rods developed by Kirchoff and Love at the turn of the previous century. These results further support the concept of chromosomes as mechanical objects and suggest specifically that the concept of chromosome stress cycling extends to chromosome axes as well as to bulk chromatin.
More generally, these findings support a new paradigm for the nature of chromosomal processes. Even spacing is an advantage for all basic features of chromosomes, e.g. DNA replication initiation events; axial compaction; and loop organization, all of which exhibit a tendency for even spacing, with events occurring at different positions in different individual cells. The dispositions of chromosomes in discrete territories could potentially represent an analogous pattern in three dimensions. We propose that mechanically-based spatial patterning underlies many or all of these fundamental features of chromosomes. (Chu et al., submitted).
Future Studies. We are now poised for further studies that include: (i) experimental tests (e.g. via mutant perturbations) of our torsional stress model in relation to theories for elastic rods as developed by SEAS colleague John Hutchinson; (ii) application of a new speckle microscopy approach involving fluorescent nucleotide labeling to probe compaction/expansion cycles and metaphase compaction, and (iii) development a mechanoluminescent nanoscale sensor of in vivo stress patterns which, when combined with other imaging tools, will provide an entirely new perspective on global chromosomal patterns and processes.
Other Research Interests