A polymer model for the structural organization of chromatin loops and minibands in interphase chromosomes

Abstract

A quantitative model of interphase chromosome higher-order structure is presented based on the isochore model of the genome and results obtained in the field of copolymer research. G1 chromosomes are approximated in the model as multiblock copolymers of the 30-nm chromatin fiber, which alternately contain two types of 0.5- to 1-Mbp blocks (R and G minibands) differing in GC content and DNA-bound proteins. A G1 chromosome forms a single-chain string of loop clusters (micelles), with each loop approximately 1-2 Mbp in size. The number of approximately 20 loops per micelle was estimated from the dependence of geometrical versus genomic distances between two points on a G1 chromosome. The greater degree of chromatin extension in R versus G minibands and a difference in the replication time for these minibands (early S phase for R versus late S phase for G) are explained in this model as a result of the location of R minibands at micelle cores and G minibands at loop apices. The estimated number of micelles per nucleus is close to the observed number of replication clusters at the onset of S phase. A relationship between chromosomal and nuclear sizes for several types of higher eukaryotic cells (insects, plants, and mammals) is well described through the micelle structure of interphase chromosomes. For yeast cells, this relationship is described by a linear coil configuration of chromosomes.

Figure 1

A mammalian G1 chromosome is approximated as a multiblock copolymer containing two types of polymer blocks with different GC contents. Light and dark chromatin segments are R and G blocks, respectively.

Figure 2

Schematic drawing of a micelle in a G1 chromosome. Dark and light chromatin blocks are G and R minibands, respectively. Segments drawn with free ends can be either chromosome ends or intermicelle links. The circle represents the micelle core (see inset), where loop termini are located. The dark dots at loop termini represent multiprotein complexes, e.g., replication complexes.

Figure 3

Schematic drawing of the dependence of 〈h_x²〉, mean-square geometrical distance, vs. M_x, genomic distance between two points on a G1 chromosome. The 〈h_x²〉 vs. M_x dependence is due to chromosome tails and intermicelle links, because the net increase in 〈h_x²〉 inside a micelle is zero. Dashed lines represent the boundaries of the experimental points. The model predicts that their slope (B_app) is f-fold shallower than the initial slope (see Eq. 6), where f is the average number of loops per micelle.