That our chromosomes can break and reshuffle pieces of themselves is nothing new; scientists have recognized this for decades, especially in cancer cells. The rules for where chromosomes are likely to break and how the broken pieces come together are only just now starting to come into view.

Researchers at Children’s Hospital Boston and the Immune Disease Institute (IDI) have helped bring those rules into clearer focus by discovering that where each of the genome’s thousands of genes lie within the cell’s nucleus – essentially, the genome’s three-dimensional organization – holds great influence over where broken chromosome ends rejoin, knowledge that could shed light on fundamental processes related to cancer and normal cellular functions, for example in immunity.

The study team, led by Frederick Alt, PhD, director of the Program in Cellular and Molecular Medicine at Children’s Hospital Boston and the IDI; and Job Dekker, PhD, co-director of the Program in Systems Biology at the University of Massachusetts Medical School, reported their results online on February 16 in the journal Cell.

In cancer cells, the process of chromosome rearrangement, or translocation – marked by stretches of DNA physically breaking and swapping – often results in the creation of new cancer-promoting “fusion” genes. Similarly, when a naive B cell starts to produce antibodies for the first time, it establishes its choice of target by breaking and recombining genes for antibody diversity.

“While chromosomal breaks and translocations are fundamental to many cancers, historically we’ve had no approaches to systematically study how they are generated,” said Alt, who is also a Howard Hughes Medical Institute investigator and the Charles A. Janeway Professor of Pediatrics and Professor of Genetics at Harvard Medical School. “About five years ago, our group set out to generate a high-throughput approach to address this important problem in cancer biology.”

To accomplish this goal, the Alt lab developed high-throughput genome-wide translocation sequencing (HTGTS, which maps “hot spots” in the genome where chromosome breaks and translocations are more likely to occur) and at a level of resolution not previously thought possible.  In early HTGTS studies, they found that broken chromosomes often rearrange within themselves, as opposed to sharing pieces across different chromosomes.

To probe these findings more deeply, his laboratory joined forces with Dekker’s to combine HTGTS with a method called Hi-C. Developed by Dekker’s group, Hi-C measures how all the sequences in the genome are organized relative to one another in three dimensions.

The combined data revealed several related but distinct principles of how genomic organization governs chromosome rearrangements. The first is based on the slight differences in how each cell organizes its genome compared to its neighbors (referred to as cellular spatial heterogeneity of genome organization).

While the genome is organized in an average fashion that is largely common across all cells of a population, each individual cell harbors small deviations from that average. This latter property allows many genes to be physically close to each other in just a small subset of cells, even if they are not close to each other in the majority of cells.

The second principle involves proximity. If two broken chromosome strands lie in close proximity within the three-dimensional space of a given cell’s nucleus, they are more likely to connect. This finding is of particular importance for translocations involving DNA sequences that do not break frequently, such those involved in translocations found in various non-lymphoid tumors.

The third principle applies the first two to DNA sequences that do break frequently (such as those that drive antibody gene rearrangements during B cell development). Such sequences tend to reshuffle with the same partner sequences in those subsets of cells where the partners lie physically close together, even if the partners do not within most cells. This can fuel recurrent translocations like those seen in many lymphoid tumors.

Together, the principles highlight the relationship between proximity, genomic organization, and break frequency. “Two sequences have to be broken and physically proximal to join,” Alt explains. “If two sequences are together in most cells and frequently broken, they will translocate in many cells.

If they are frequently together but one of them doesn’t break, or if they both break frequently but always lie on opposite sides of the nucleus, the chances that they will translocate are very low or zero. However, if both sequences break very frequently and are close together in a subset of cells, they will very frequently translocate in that subset, contributing to recurrent translocations.”

“Our finding that broken chromosome segments are more likely to join with other segments within the same chromosome, rather than other, more physically distant segments from other chromosomes, likely has great relevance to cancer genomes,” Alt continued. “For example, cancer treatments that cause breaks may preferentially lead to intra-chromosomal rearrangements.

It may also have relevance for ‘chromothripsis,’ a recently discovered phenomenon in many cancers in which the sequences of one chromosome become scrambled.”

The new understanding of the roles of physical spatial proximity and overall three-dimensional genome structure in chromosomal translocations opens up new avenues for deciphering how the way a cell’s nucleus is organized affects the genomic disarray found in cancer and other diseases characterized by chromosome reshuffling.

The study also shows the power of combining two high-throughput genomic assays – Hi-C and HGTGS – for studying how the organizational plan within the nucleus influences fundamental biological processes. ”We feel that our findings and the application of our approaches will provide a new lens through which to view the genomes of many different types of cancer,” Alt concluded.

This study was supported by the National Cancer Institute, the National Human Genome Research Institute, the Howard Hughes Medical Institute, the Leukemia and Lymphoma Society, the W.M. Keck Foundation, the Cancer Research Institute, and the German National Merit Foundation.

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SIPP International Industries, a diversified company, parent to several divisions in the food and biotechnologies industries, is pleased to announce the acquisition of the cutting-edge Cell Robotics Imaging Work Station. The acquisition was completed through the purchase of a secured note which later went into default.

The Cell Robotics Imaging Work Station will be used to combat the rising rate of global biological terrorism by remotely identifying, isolating single bacterium, and researching key pathogenic agents including anthrax, small pox and botulism. This technology will also be integrated into the company’s Z-CAC Controlled Atmosphere Cargo Container.

The Cell Robotic Imaging Work Station has many additional uses for investigators, physicians and pathologists, including early detection of cancer and monitoring patients before, during and after medical treatments.

The newly acquired technology upgrades the already successful Cell Robotics Work Station with the addition of an analytical imaging software package and new, more powerful Laser Scissors. The new software provides state-of-the-art image analysis and data management capabilities. “SIPP is planning to work diligently to improve and enhance these products,” states Gregg Pearson, Chairman of SIPP International Industries.

The Imaging Work Station still includes the well-known optical trapping laser and Laser Tweezers, but now offers a choice of three available cutting lasers, or Laser Scissors modules. The increased power of the newest Laser Scissors module will allow researchers to easily dissect fresh, frozen, or fixed tissue sections, in addition to live cells, useful for molecular analysis of biopsies.

The Cell Robotics Imaging Work Station is designed for investigators in both basic and applied research, working with stem cells, transgenic animal production and cloning, and functional genomics or proteomics. Additional imaging upgrades are available to include automated cell identification and deconvolution.

“We are very excited about the Cell Robotics Imaging Work Station. This cutting-edge technology will further help the medical community at large as well as assist investigators in combatting the rising use and threat of biological terrorism. We anticipate this acquisition to accelerate our revenues in the near-term,” states Gregg Pearson.

“The technology also provides a perfect synergy with the Cell Robotics Pathology Work Station. As the industry is evolving toward molecular medicine, the goal of modern physicians and pathologists is to precisely monitor a patient before, during and after treatment.

The Cell Robotics Pathology Work Station is designed to provide pathologists with new tools for the retrieval of specific cells to allow molecular analysis of biopsies. Once the specimen of interest is identified by the pathologist, the laser automatically cuts around it using the new auto-cut software,” says Pearson.

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