Gleaning from the natural process of X chromosome inactivation, scientists recently discovered a way to “turn off” the extra copy of chromosome 21 in Down syndrome, a strategy that might one day cure this disorder.

The 23 pairs of chromosomes  in the human genome is the product of nature’s elusive calculations to caliber the precise levels of gene expression in the cell- a calibration crucial for the normal function of human tissues and organs. The presence of one too many chromosomes, such as the extra chromosome 21 in Down syndrome, can have serious consequences. Among the most prominent consequences include intellectual impairment, heart defects and even early Alzheimer’s disease.

One approach to “cure” Down syndrome would be to shut down the extra chromosome 21, the root cause of this disorder. Taking this approach in a recent study reported in Nature this week, scientists at the University of Massachusetts discovered that the gene involved in X-chromosome inactivation, a natural process by which one of the two X chromosomes in the female genome is turned off, can be used to turn off the extra chromosome 21 in Down syndrome.   

The gene, called the X-inactive specific transcript (XIST), is expressed in one of the X-chromosomes during early female development. XIST encodes a non-coding ribonucleic acid (RNA) that silences gene expression by covering the entire X-chromosome with a RNA blanket. The RNA blanket triggers a series of chromosomal changes to silence gene expression, including chemical modifications that cause the DNA to wrap more tightly around histones (the DNA “spools” in the chromosome). The result is a condensed X chromosome (known as the Barr body) in which gene expression is silenced- an effect due to the inaccessibility of the condensed chromosome to the cell’s gene expression machinery.

Dr. Jeanne Lawrence, the senior author of this Nature paper, wondered whether XIST could be used to silence the entire chromosome 21, much like X chromosome inactivation.  To test this idea, Lawrence’s team inserted the XIST gene into the extra copy of chromosome 21 in induced pluripotent stem cells (iPSCs) derived from Down syndrome patients. These iPSCs are defined by their ability to differentiate into any tissue in the body, and are generated by reprogramming skin cells from Down syndrome patients using a process invented by Dr. Shinya Yamanaka in 2006. To successfully insert this rather large XIST gene specifically into the extra chromosome 21 of Down syndrome iPSCs, Lawrence’s team used a robust editing enzyme called the zinc finger nuclease, an enzyme that can insert genes into chromosomes with high precision.  To control the activation of the XIST gene, the researchers further designed the insertion so that XIST expression can be induced by the drug doxycycline.

Upon inducing XIST gene expression in Down syndrome iPSCs with doxycycline, Lawrence’s team discovered that the XIST expression can successfully inactivate the extra chromosome 21, turning it into a condensed Barr body similar to an inactivated X chromosome.  

What’s more, the chromosome 21 inactivation was enough to eliminate the debilitating symptoms of Down syndrome.  For example, the researchers found that iPSCs from Down syndrome patients tend to overexpress genes found in chromosome 21, including amyloid peptide protein (APP), a gene that are aberrantly expressed in Alzheimer’s disease. Moreover, these iPSCs typically differentiate into defective neurons with deformities called rosettes, a feature that may explain the intellectual disabilities observed in Down syndrome. When the researchers inactivated the extra chromosome 21 in Down syndrome iPSCs with doxycycline, they were able to restore the normal expression of chromosome 21 genes in these cells. Moreover, these iPSCs also differentiated into “normal” neurons in culture, with no signs of deformities associated with Down syndrome.

The results suggest that XIST-induced inactivation of chromosome 21 may be an effective strategy to eliminate the symptoms of Down syndrome, especially the neuronal defects responsible for intellectual disabilities.  According to Lawrence, the study presents the first proof-in-principle that chromosome 21 inactivation may be an effective treatment for Down syndrome, an exciting prospect that will give hope to millions of Down syndrome patients across the globe.


The Nature paper:  Jiang et al. (2013). Translating dosage compensation to trisomy 21. Nature. doi:10.1038/nature12394