Insertion of a single gene, XIST, epigenetically silences the extra chromosome 21 responsible for Down syndrome. This result, obtained via the study of laboratory cultures of patient-derived stem cells, is the culmination of years of work by a team of scientists led by Jeanne Lawrence, Ph.D., professor of cell and developmental biology at the University of Massachusetts Medical School.

The team’s inspiration was dosage compensation, the natural process that silences one copy of the female mammals’ two sex-determining chromosomes during embryonic development. Dosage compensation ensures that male and female cells contain roughly equal amounts of X chromosome-encoded gene products, even though the cells of females have double the number of X chromosomes that occur in males.

In earlier work, Dr. Lawrence’s team investigated dosage compensation by studying the X-inactivation gene, or XIST, which encodes a large noncoding RNA molecule. In laboratory cultures of cells, this molecule was shown to cover the surface of one of the X chromosomes of female mammals. XIST’s actions permanently blocked the expression of the genes on the affected X chromosome.

More recently, in gene silencing work described in a paper published July 17 in Nature, Dr. Lawrence’s team mimicked this process by inserting the XIST gene into the gene-rich core of the extra chromosome 21 in lab cultures of pluripotent stem cells from patients with Down syndrome. In this paper, the authors wrote: “The XIST noncoding RNA coats chromosome 21 and triggers stable heterochromatin modifications, chromosome-wide transcriptional silencing, and DNA methylation to form a chromosome 21 Barr body.”

At that time, the authors noted that they had created a “tractable, inducible system to study human chromosome silencing.” With respect to trisomy silencing, the model’s immediate impact was to provide “a new means to define the poorly understood cellular pathways deregulated in Down’s syndrome, creating the opportunity to derive and study various patient-compatible cell types potentially relevant to Down’s syndrome therapeutics.”

Additional progress on this work was described by Dr. Lawrence on October 22, at a meeting of the American Society of Human Genetics. “Remarkably, the RNA localized across and comprehensively silenced one of the three chromosome 21s, as shown by eight different methods, including molecular, cytological and genomic,” said Dr. Lawrence.

Dr. Lawrence added the XIST-induced changes in gene expression are not limited to chromosome 21, but are genome wide: “In fact, the results indicate that the most prominent changes are in genes not encoded on chromosome 21.”

Providing additional perspective about the implications of these results, Dr. Lawrence stated that genome silencing was a promising approach in studies of Down syndrome because it had the potential to identify the cellular pathologies and genome-wide pathways most directly perturbed by trisomy 21, “distinct from pervasive genetic and epigenetic variation between cell isolates and subclones.” Silencing of trisomy 21 by manipulation of a single gene in living cells in vitro, said Dr. Lawrence, surmounts the first major obstacle to development of potential “chromosome therapy.”

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