ddn Cancer Research News Exclusive: Jewels from junk
03-13-2013
by Kelsey Kaustinen  |  Email the author

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LA JOLLA, Calif.—The decoding of the human genome unlocked a wealth of information about human biology, including the discovery that less than 2 percent of our genome actually codes for proteins. Following the Human Genome Project, most research attention was focused on the coding DNA, dismissing the "junk" or non-coding DNA as superfluous. But more recent research, including the Encyclopedia of DNA Elements (ENCODE) project, has shown that even junk DNA plays significant roles in our biological functions.  
 
Among that all that "junk" are small stretches of DNA known as "pseudogenes," which boast sequences nearly identical to those of standard genes yet are non-coding, and according to a new study from The Scripps Research Institute, some of those pseudogenes regulate the activity of the phosphatase and tensin homolog (PTEN), a cancer-related gene.
 
The study was lead by Scripps scientist Kevin Morris, Ph.D., in collaboration with scientists at the Karolinska Institutet in Stockholm, Sweden, and the University of New South Wales in Sydney, Australia.
 
 
The researchers demonstrated that pseudogenes are capable of influencing PTEN's activity, an exciting discovery considering the gene's identification as a tumor suppressor gene. Though pseudogenes don't code for proteins, this latest work by Morris and colleagues has revealed that the genetic sequences exert control over the activity of various genes. Pseudogenes that have sequences in common with PTEN can regulate the gene by either suppressing the "promoter" for PTEN and preventing it from being expressed, or soaking up PTEN-targeted regulatory microRNAs that affect the gene after its genetic transcripts are expressed.  
 
According to Morris, two other papers "on pseudogenes regulating protein-coding genes" were published previous to this most recent Nature Structural & Molecular Biology study, one of which was from Morris' group. One paper focused on PTENpg1 sense, showing that "the PTEN pseudogene 1 (PTENpg1) controls micro RNA targeting of the PTEN protein expression, e.g. transient translational control of protein expression in the cytoplasm." The other paper from Morris' group showed that Oct4—octamer-binding transcription factor 4, which plays a pivotal role in the differentiation of embryonic stem cells—is controlled by a pseudogene in terms of epigenetics and transcription.  
 
Pseudogenes, says Morris, can be targeted directly by using antisense RNAs, oligos or RNAi, and it is possible to control both of PTEN's functions.
 
"We can control both aspects of the pseudogenes' effects, and both are equally easy to modulate, but the targeting the transpirational regulatory PTENpg1 antisense RNA alpha variant is the way to go, as it leads to activation of PTEN transcription, e.g., we turn up PTEN," Morris explains. "The targeting of the PTENpg1 sense only transiently affects PTEN. In brain tumors where PTEN is suppressed, stable activation can significantly prolong life if not double the survival following removal of the tumor."
 
Morris cautions that targeting pseudogenes as a therapeutic approach has some technical issues, primarily in the sense that developing a drug that can target pseudogenes would have to be delivered directly to the cells where it is needed without affecting healthy tissues. Even so, therapeutics that could activate PTEN could make waves in several types of cancer, says Morris, including glioblastomas and melanomas, as well as stroke and head injuries.  
 
Morris and his colleagues will be continuing this research in several directions, he adds, including such fields as HIV latency, cystic fibrosis and autism, in addition to cancer.  
 
"The coolest thing of this work is it's an entirely unrecognized mode of action that is controlling gene expression and epigenetic heritability, really a far-out paradigm shift that now allows us to selectively activate gene expression," Morris concludes.  
 
The study, "A pseudogene long non-coding RNA network regulates PTEN transcription and translation in human cells," appeared in the Feb. 24 issue of Nature Structural & Molecular Biology, and was supported by the National Institute of Allergy and Infectious Disease, the National Cancer Institute, the Swedish Childhood Cancer Foundation, the Swedish Cancer Society, Radiumhemmets Forskningsfonder, the Karolinska Institutet Ph.D. support program, Vetenskapsrådet and the Erik and Edith Fernstrom Foundation for Medical Research.
Code: E03121300

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