A paper in the August 24 issue of Proceedings of the National Academy of Sciences, U.S.A., from the Kleckner lab provides a new theory of chromosome function that may have important implications for research in the field. (See Kleckner et al., “A mechanical basis for chromosome function.”) The paper represents a collaboration of Dr. Kleckner with several researchers and in particular Dr. John Hutchinson, Professor and Associate Dean for Academic Programs in the Department of Engineering and Applied Sciences at Harvard.
Kleckner et al. hypothesize that mechanical stress forces govern the mitotic and meiotic programs, which comprise cycles of chromatin expansion and contraction. Here, Sordaria chromosome axes in meiotic prophase (stained with Spo-76 GFP [source: Denise Zickler]) are stiffer or floppier in periods of expansion or contraction, respectively.
The Kleckner laboratory studies meiosis, the specialized cellular program by which a diploid cell generates haploid gametes as required for sexual reproduction. A prominent feature of this program is recombination (“crossing-over”) between homologous maternal and paternal chromosomes. Several types of analysis show that the distribution of crossovers along a given chromosome is strikingly nonrandom. One aspect of this is the phenomenon “crossover interference”: when a crossover is present at one position, there is a reduced probability that another crossover will also be present nearby. Since crossovers are selected from many precursor sites along the chromosome, this is a particularly interesting phenomenon because it implies the existence of communication along the chromosome, the mechanism of which is entirely unknown.
In their recent paper, Kleckner and colleagues show that this and other features of meiotic crossover distributions could be economically explained if the molecular process that designates a particular precursor site to be a crossover was driven by mechanical forces (stresses). Among other effects, such models provide for communication along a chromosome because a local change in the level of stress, either an increase or a decrease, tends automatically to redistribute outward from its point of imposition. The robustness of this suggestion is documented using an appropriately analogous system from the physical world whose mechanical properties can be described mathematically and modeled. At suitable values of key parameters, a close correspondence can be found between the predicted distribution of stress-promoted events in the model system and those observed experimentally for crossovers or certain correlated cytological features.
The Kleckner paper goes on to point out that the unique types of spatial patterning characteristic of meiotic crossovers are also exhibited by a number of basic chromosomal processes common to all types of cells including firing of replication origins, development of chromosome “compartments,” and many other organizational features including nucleosome positioning and axial coiling. The suggestion is therefore made that mechanical effects might be of general importance to basic chromosome function.
The authors further propose that the mechanical forces needed for such effects may arise from programmed tendencies for expansion of the DNA/chromatin fiber. Rather than being able to occur freely, as would be the case for a segment of chromatin in a test tube, expanding chromatin would instead “caged” either by external constraints (e.g., other chromatin) or internal constraints (e.g., an intersegment meshwork mediated by nucleosome/nucleosome contacts and/or chromatin structure components). Such caging would put the constraining components under mechanical stress, primarily from “pushing forces,” and these pushing forces could do mechanical work. Specific potential effects of such forces are described.
Kleckner and colleagues also go on to synthesize relevant observations from the chromosome literature. They find that the mitotic cell cycle and meiosis are both characterized by alternating sequential cycles of chromosome expansion and contraction. This analysis also reveals a previously unsuspected relationship between the two programs, specifically with regard to meiotic prophase, which is greatly prolonged as compared to its mitotic counterpart and is the period of key meiosis-specific interactions between homologous chromosomes. Meiotic prophase appears to be directly related to (and thus may be evolved from) the latter periods of the mitotic cell cycle, prometaphase through telophase/G1. In addition, the Kleckner et al. paper makes the case that periods of expansion are characterized by events predicted to result from increased mechanical stress whereas periods of contraction are characterized by the opposite types of effects.
A separate recent study from the Kleckner laboratory (see Boerner et al news item on MCB website) has further pinpointed the time at which crossover sites are designated during meiosis. The critical point is at the end of period of global chromosome expansion and, integration of the predicted effects of chromatin expansion with the known structure and organization of meiotic chromosomes at the relevant point has led to a specific model for crossover designation and accompanying patterning, including interference, as well as for a new model for the role of a prominent but mysterious meoitic chromosomal structure, the synaptonemal complex (Boerner et al.).
Kleckner and colleagues conclude their paper with consideration of some of the broader implications of their “chromosome stress hypothesis.” While many aspects of meiosis and other chromosome activity are coming to be understood biochemically piece by piece, the Kleckner et al. paper proposes a new way of integrating the vast and rapidly accumulating details. In addition, as the authors note, “An attractive feature of this model is that the DNA plays a governing role not only via its information content but also via its intrinsic mechanical properties.” By posing questions in a new way, this proposal promises to open up new avenues for research into chromosome structure and function.