Close your eyes and try to imagine medical treatment in the future. I envision sophisticated robots wielding lasers that precisely eliminate deadly tumors. I predict that insight from genome wide association studies (GWAS) will explode allowing for personalized human genomics to move center stage. Effectively identifying genetic abnormalities has the potential to take the guesswork out of choosing the most effective drug treatment for an individual. In my wildest daydreams, I imagine a technology that would enable silencing of entire extra chromosomes associated with developmental disorders.
Down syndrome is the leading genetic cause of mental retardation and is attributed to having three copies of chromosome 21. This extra chromosome leads to increases in expression of genes that give rise to early onset of Alzheimer’s disease and cognitive impairments in Down syndrome patients. Silencing chromosomes might not be as far off in the future or as science fiction-based as we might think. In a cutting edge paper published in Nature, researchers successfully inactivated the genes localized to chromosome 21 in pluripotent stem cells, providing the first hope for chromosome inactivation-based therapy.
In the United States alone, 1 in 300 infants will have a chromosome abnormality – half of which will be Down syndrome. The researchers were motivated to uncover a mechanism behind silencing the extra chromosome given the severity of intellectual disabilities associated with this syndrome. In a clever experiment, they took advantage of the human body’s natural mechanism to ensure that only one X chromosome is expressed. All female mammals silence one of the two X-chromosomes with the X-inactivation gene (XIST). XIST activation causes the surface of the chromosome to be coated; this coating blocks other genes from being expressed and effectively silences one chromosome.
The challenge of this study was inserting XIST into one copy of chromosome 21. The researchers took advantage of zinc finger nuclease (ZFN) driven targeted addition – a technique used to insert a gene into a specific location on a chromosome. The XIST gene is 17 kilobases and to date is the largest gene inserted into a chromosome region.
The idea behind this experiment was to insert a single gene that would epigenetically silence the entire chromosome. The researchers harnessed the naturally occurring silencing capacity of XIST and applied it to chromosome 21. They inserted the X-inactivation gene into one copy of chromosome 21 in stem cells from a Down syndrome patient. During development, XIST RNA is able to silence and inactivate the X-chromosome through a series of heterochromatin modifications that are identifiable in the chromosome as a condensed Barr body. Heterochromatin is a tightly packed form of DNA that changes the ability of proteins to bind to DNA and alter transcription, thus turning genes on and off.
Using this technology, the team was able to silence the APP gene on chromosome 21. Amyloid precursor protein (APP) when mutated causes a build up of beta-amyloid plaques that lead to the early onset of familial Alzheimer’s disease. The expression of XIST resulted in the complete downregulation of this gene. Helping to restore normal levels of APP has the potential to prevent the early-onset of Alzheimer’s disease in Down syndrome patients. The reason to get excited about this research is it opens the door for gene therapy research that could correct the chromosomal abnormalities associated with Down syndrome and other chromosomal disorders (trisomy 13 and 18) that are often fatal. While these findings are still only relevant in stem cells, it is the first step on the way to the treatments of the future that were once only the subject of science fiction.
Jiang J., Jing Y., Cost G.J., Chiang J.C., Kolpa H.J., Cotton A.M., Carone D.M., Carone B.R., Shivak D.A., Guschin D.Y. & Pearl J.R. (2013). Translating dosage compensation to trisomy 21, Nature, 500(7462) 296-300. DOI: 10.1038/nature12394
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