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These findings, published in the Proceedings of the National Academy of Sciences (PNAS) , are the first to show how this chromosomal mutation likelycontributes to early development of prostate cancer -- and suggestsa model for how other chromosomal translocations, common to manytumor types, are linked to cancer formation and growth. "This is likely a phenomenon that occurs in many types ofcancers when oncogenic fusion genes are over-expressed," saysthe study's senior author, Dr. Mark A. Rubin, The Homer T. HirstProfessor of Oncology in Pathology and vice chair for experimentalpathology at Weill Cornell Medical College. Dr. Rubin adds that if such an oncogenic protein has the power tothrow the switch on thousands of genes, a novel treatment may beable to turn that switch off. "If we understand how thisworks, then we may be able to borrow that trick to target manygenes simultaneously. This discovery would hold a lot of promisefor cancer therapy," he says. The study also adds to the growing understanding of how remodelingof the chromatin regulates genes linked to cancer, says the study'slead author, Dr. David S. Rickman, assistant professor of pathologyand laboratory medicine at Weill Cornell Medical College. Thegenome's DNA, along with specialized proteins, has to be packedinto the chromatin bundle so that it can fit inside a cell'snucleus, and when genes need to be expressed, the chromatin opensup a bit, allowing transcription. Emerging evidence suggests that,within this package, the genome organizes itself according to anon-randomly-assembled, 3-D architecture of hubs and domains thataffect when and where individual genes are turned on. This study shows the oncogenic ERG protein, produced by the ETSprostate cancer fusion gene, binds to specific sites in the genome,which then forces the 3-D genome architecture to vastly change,creating different hubs and domains, Dr. Rickman says. This resultsin additional chromosomal translocations, as well as a coordinatedexpression of genes known to be relevant to aggressive prostatecancer, he says. The research shows just how complex genetic regulation really isand how distortions in this process can lead to cancer, says Dr.Rubin, who is also a professor of pathology and laboratory medicineand professor of pathology in urology at Weill Cornell MedicalCollege. "We used to think everything related to gene expression waslinear, that one promoter affected the gene located right next toit," he says. "Now we are beginning to understand thatwhat happens in the 3-D space of tightly bundled DNA is alsoimportant -- how DNA opens up and undergoes changes thatefficiently turn on whole sets of genes that aren't locatedanywhere near each other." It Takes a Village -- of Scientists Reaching these findings required a collaborative team ofscientists, says Dr. Rubin, who co-discovered the ETS fusion gene.For this project, he sought the expertise of Dr. Rickman and Dr.Olivier Elemento, an assistant professor in the Department ofPhysiology and Biophysics and assistant professor of computationalgenomics in the Institute for Computational Biomedicine at WeillCornell Medical College, and a co-senior author of the paper. Dr.Elemento and his lab provided the expertise in computationalbiology and mathematical analysis needed to interpret the complexdata produced by the experiments run by Dr. Rickman, his lab andmembers of the Rubin laboratory. Joining them were nine other scientists from Weill Cornell MedicalCollege, and two from Mount Sinai School of Medicine. Dr. Elemento, Dr. Rickman and their laboratory colleagues usednumerous techniques to understand the effect of the ERGoncoprotein. They first used an experimental technique called Hi-Cto query chromatin interactions throughout the genome."Chromatin interactions are inherently complex and it is easyto grasp why this is so," says Dr. Elemento. "There areabout 25,000 known genes in the human genome therefore there arepossibly 25,000 x 25,000 interactions between genes -- which is 625million -- and that is only scratching the surface." To treat the high volume of data the researchers needed to developnew statistical methods to detect chromatin interactions and thechanges that occur when ERG is over-expressed. Then, to understand why these chromatin interaction changesoccurred in the first place -- what it is that ERG does to generatenew interactions or abolish existing ones -- they performedadditional experiments, which produced even more data. They used atechnique called ChIP-seq to map where on the genome ERG likes tobind, and then used the RNA-seq tool to determine which genes areexpressed or shut down when ERG is present. More analyses were needed to identify genes and regions on thegenome whose interaction patterns changed most when ERG wasover-expressed. Finally, they reached what Dr. Elemento called ashocking revelation: "ERG binds very often near the geneswhose interaction patterns change the most, thus indicating thatERG directly mediates the interaction by binding to theseregions." The researchers then discovered that genes whose expression wascollectively increased or shut down, and which were involved inchromatin interactions, were those that are involved in cellinvasion, a key feature of aggressive prostate cancer. "Wethus think that ERG may contribute to prostate cancer phenotype byrearranging chromatin interactions to promote the expression ofthese key malignancy genes," Dr. Elemento says. ERG also seems to push the formation of new chromosomaltranslocations, he says. "This is exciting because it pointsto a completely novel, non-transcriptional role for ERG incancer," Dr. Elemento says. "We think that it is possiblethat many genes like ERG -- which bind to the DNA -- could promotethe formation of novel genetic alterations by rearranging chromatininteractions." Dr. Rickman agrees, "These findings extend beyond the contextof the prostate as many driving genetic lesions in other cancertypes involve abnormal expression of transcription factors due togenomic alterations." The researchers are now conducting studies to unravel the mechanismthat accounts for these architectural changes. "Achieving thiswill provide a new understanding of cancer and novel ways to treatand prevent its progression," Dr. Rickman says. The work was supported by funding from a U.S. Department of DefenseNew Investigator Award, a National Science Foundation CAREER Grant,a National Institutes of Health National Cancer Institute Grant andby the Starr Cancer Consortium. Other co-authors include Dr. T. David Soong, Benjamin Moss, Dr.Juan Miguel Mosquera, Jan Dlabal, Dr. Stéphane Terry,Theresa Y. MacDonald, Dr. Karen Bunting, Dr. Francesca Demichelisand Dr. Ari M. Melnick from Weill Cornell Medical College; andJoseph Tripodi and Dr. Vesna Najfeld from Mount Sinai School ofMedicine. The e-commerce company in China offers quality products such as Outdoor Flash Photography Manufacturer , Macro Led Ring Light, and more. For more , please visit Studio Flash Lighting today!
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