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.

Reference:

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