DNA sequencing, fluorescence microscopy help render bacterial chromosome in 3-D

Researchers at the University of Massachusetts Medical School (Worcester, MA), Harvard Medical School (Boston, MA), Stanford University (Palo Alto, CA) and the Prince Felipe Research Center (Valencia, Spain) have rendered a complete 3-D structure of the bacterium Caulobacter crescentus's chromosome, revealing new insights into the function of genetic sequences responsible for the genome's shape and structure.

Knowing that the 3-D shape of a cell's chromosome plays a role in how genetic sequences and genes are regulated, the research team used high-throughput chromatin interaction detection, next-generation DNA sequencing, computational modeling, and fluorescence microscopy to build the first 3-D model of the architecture of the bacteria's chromosome and analyze the resulting structures. The approach revealed novel characteristics of a specific genetic sequence called the parS site, which helps to define the chromosome's shape.

Dr. Job Dekker, professor of biochemistry & molecular pharmacology at the University of Massachusetts Medical School, and colleagues used "5C" technology to map more than 28,700 contact points in the Caulobacter crescentus's genome and used these contacts to approximate spatial distance in the folded chromosome. Plugged into a computational model, these contact points yielded a structural model of the bacterial chromosome—ellipsoidal in shape with arms helically arranged on either side. The work demonstrates that combining 5C maps with their method can produce genome-wide 3-D models in unprecendented detail, says Dr. Marc A. Marti-Renom, a computational biologist who leads the Structural Genomics Laboratory at the Prince Felipe Research Center.

Their method—which uses fluorescent microscopy—illustrates that the parS sequence, located in the pole of one arm of the chromosome, potentially served as an anchor for the genome and were instrumental in defining its overall structure.

To unravel the role the parS site plays in the 3-D organization of the chromosomal structure, the team constructed mutant bacteria in which the parS site had been moved away from its normal position. Building 3-D models of the shape of the mutated bacteria, they observed a change in the chromosome's structure; the entire genome had rotated clockwise.

Changing the position of the parS site had resulted in a large-scale reorganization of the chromosome's shape that repositioned these sites at the cell's poles. Moving sequence elements that are no larger than 500 base pairs led to a change in the conformation of all of the 4 million base pairs of the chromosome, notes Mark Umbarger, a postdoctoral fellow at Harvard Medical School involved in the study.

The study illustrates how an investigation of 3-D genomic structure can provide insights into how the complex relationships between genome sequence and structure can impact function. By studying genomic architecture, scientists could potentially identify new classes of genomic sequences that are important in chromosome function and structure, says Dekker.

The work is published this week in Molecular Cell: http://www.cell.com/molecular-cell/abstract/S1097-2765%2811%2900759-3#Summary.

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