The Loop-extrusion model
The genome of living organisms--the totality of the DNA that carries hereditary instructions for life--is more than just a string of chemical "letters". In reality, genomes in all organisms are physically organized into complex structures that are crucial for their function. For instance, the varied genomic structures in different human cells (ex. neurons, blood cells) ensures that these cells can perform different tasks despite sharing the same underlying DNA sequences. Abnormalities in the structure of genomes have been linked to various diseases, including cancer. For these reasons, it is crucial to understand what are the mechanisms used by cells to organize their genome. Our research aims to address this question.
The genome is structured in a hierarchical manner. At the smallest scale, DNA is wound around proteins to form a structure known as chromatin. This chromatin is, in turn, organized into domains, or continuous segments of DNA (a few million base pairs long) that tend to associate with each other. Domain structures are important in regulating whether genes are turned on or off in a cell. For instance, inactive genes can be packed into tight domains that are hard for cellular machinery to access, while active genes associate into domains that are easier to access. At an even larger scale, the genome is folded up to ensure that it can fit inside the cell. In humans, DNA would span a few meters if fully stretched out, yet it must be compressed into a micrometer-sized cell nucleus. This remarkable task is analogous to fitting a string the length of a skyscraper into a sesame seed!
Our work has proposed a simple mechanism to explain the formation of chromatin structures, particularly at the intermediate length scale of domains. Namely, we hypothesize that chromatin within a domain is united by loops. As these loops grow larger and larger with the help of proteins, more distant regions of the DNA can be brought into contact, allowing large-scale organization to be formed. We have run simulations of this process, which we call loop-extrusion, and shown that it successfully reproduces various genomic structures that have been observed experimentally. This suggests that a loop-extrusion process may play important roles in organizing the genome into functional structures in living cells. Our current research aims to further test this theory by evaluating whether it may create genomic structures, and thus promote crucial regulatory processes in a wide range of organisms.
Model of loop extrusion by condensins:
Top row, the update rules used in simulations: (A) a condensin extrudes a loop by moving the two ends along the chromosome in the opposite directions, (B) collision of condensins bound to chromosomes blocks loop extrusion on the collided sides, (C) a condensin spontaneously dissociates and the loop disassembles; (D) a condensin associates at randomly chosen site and starts extruding a loop. Bottom row, (E) we use polymer simulations to study how combined action of many loop extruding condensins changes the conformation of a long chromosome.
Top image: Simulations of sister chromatids separation by the action of loop extrusion.
Credit: Dr. Anton Goloborodko