ALZFORUM: Networking for a cure (18 Apr 2014)
Down’s Syndrome Loosens Regulation of the Entire Genome
Gwyneth Dickey Zakaib

For decades, scientists thought that Down’s syndrome resulted from genes carried on the extra copy of chromosome 21 that causes the disorder. More recently, researchers have recognized that gene expression becomes altered throughout the entire genome. Now, researchers led by Stylianos Antonarakis at University of Geneva Medical School, Switzerland, examine these genetic changes in minute detail. By examining a set of monozygotic twins, one of whom had Down’s syndrome, they were able to see that cells with an added chromosome 21 exhibit a distinct pattern of gene dysregulation across the genome. Chromosomal areas that are usually highly expressed quiet down, while those that are normally silent perk up. As the researchers report in the April 17 Nature, the findings suggest that epigenetic changes could be at play.

“The authors may have hit upon a genetic mechanism that could explain some of the specific clinical and neurobiological phenotypes you see in Down’s syndrome,” said Elliott Mufson, Rush University, Chicago, who was not involved in the study. “Whether it’s going to lead to a game-changing effect in understanding the disorder is hard to know.”

Researchers have known for some time that an extra copy of chromosome 21 causes genome-wide changes in gene expression (see Vilardell et al., 2011). Just how the genes are disrupted remained a mystery, however, because high-background genetic variation between people masks the effects of an extra chromosome. Antonarakis and colleagues had a rare opportunity to circumvent this limitation when they became aware of a unique pair of monozygotic twin fetuses that had been aborted at 16 weeks, one with trisomy 21 and the other without. These two were genetically identical, save for that one extra chromosome. By examining gene expression differences between them, the researchers were able to avoid the background variation that occurs between unrelated people.

First author Audrey Letourneau and colleagues measured levels of messenger RNA from four separate samples of skin cells from each of the twins. They found that an alternating pattern of expression changed throughout the genome of the twin with Down’s. Compared to the normal twin, some groups of genes were activated while others were suppressed. These up- and downregulated blocks lay next to each other on all chromosomes. The authors called these regions gene expression dysregulation domains (GEDDs). Remarkably stable, these GEDDs persisted when the researchers derived induced pluripotent stem cells from skin fibroblasts. To the authors’ surprise, the Ts65Dn mouse model of Down’s syndrome showed GEDDs that affected the same genes, even though they lie on different chromosomes in mice and humans.

The GEDDs overlapped with specific chromosomal regions called lamina-associated domains (see Guelen et al., 2008) and early replication domains (see Hansen et al., 2010). LADs are areas of low gene expression that are marked by suppressive patterns in the local chromatin; conversely, early replication domains are highly active regions of the genome. In the trisomic twin, as well as the Ts65Dn mouse, LADs were unusually active, whereas early replication domains were curiously subdued (see image below). “The result is a genome-wide flattening of gene expression,” wrote Benjamin Pope and David Gilbert of Florida State University, Tallahassee, in an accompanying News and Views article.

Genomic domains that are normally associated with low or high levels of gene expression are respectively up- or downregulated in Down’s syndrome. [Image courtesy of Nature.]

The authors are unsure what drives this. They found more methylation of histone H3 (H3K4me3) in the areas of upregulated genes, suggesting that the DNA there was more accessible.

Antonarakis proposes that an extra copy of one or more particular genes on chromosome 21 leads to widespread chromatin changes that disrupt transcriptional regulation and explain some of the phenotypes in Down’s syndrome. Alternatively, the mere presence of extra DNA in the nucleus could be the reason, he said. That would suggest other trisomies could lead to similar genome modifications. Antonarakis’ team is testing that possibility by comparing trisomic and normal cells from people who have a mix of these cells in their bodies. People with cancer often accumulate trisomic cells.

“Clearly trisomy has an impact on the entire genome,” said Roger Reeves, Johns Hopkins University School of Medicine, Baltimore. “Though it is sometimes subtle in magnitude, it has a profound effect.”—Gwyneth Dickey Zakaib

Nature: Domains of Genome-wide gene expression dysregulation in Down's syndrome (2014)