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Geography Matters in the Nucleus

For gene expression, it's all about location, location, location.

September 2009 -- Karen Reddy is a biologist. But when she describes her research on gene expression and nuclear architecture, she begins to sound a bit like a realtor. Different “neighborhoods” in the nucleus are more desirable than others—at least when it comes to gene expression, Reddy says. In one nuclear region, a gene may be “turned on,” while in another, the same gene may be “turned off.”

“I call it the real estate hypothesis,” says Reddy, who joined the Department of Biological Chemistry in January of this year. “It’s all about location, location, location.”

The nuclear location that currently interests Reddy most is the area along the inner surface of the bilayered nuclear membrane. Parts of this region, she believes, are a sort of dead zone for gene activity, nuclear neighborhoods that silence gene expression. To elaborate on this hypothesis, she is launching a study to map every point of contact between the genome and the nuclear membrane, a project that is essentially something like a puzzle: Of the meters and meters of DNA that are stuffed into the tiny cell nucleus, which regions are positioned along the miniscule surface area of the nuclear envelope?

Such research could help answer the fundamental question of developmental biology: Given that each cell of an organism has identical genes, how and why do cells diversify? Part of the answer, says Reddy, may be that the cells use the neighborhood of the nuclear membrane as a sort of hiding place for genes no longer needed or not needed at the moment. For example, an immature germ cell might keep certain genes tucked away along the underside of the nuclear membrane, their activity repressed, until the time comes for the cells to mature.

Reddy is exploring mechanisms that can be defined as epigenetics, but they broach a novel area of the discipline, notes Andy Feinberg, director of the IBBS Epigenetics Center, of which Reddy is a faculty member. Most epigeneticists have focused on chemical changes, such as methylation, that can silence or activate a gene. Fewer scientists have explored the role that a gene’s geography plays in its expression. “It’s the next big frontier,” says Feinberg. “And Karen is at the cutting edge.”

Reddy’s own interest in the field began in graduate school at the University of Illinois College of Medicine, where she was studying Drosophila muscle development. “We were doing the canonical approach—take part of a gene, chop apart the enhancer, study the sequences,” says Reddy, “and ask how they were important in regulating the gene.”

But Reddy started thinking that gene sequences—pure linear information—did not hold all the answers. Instead, a gene’s location in three-dimensional space might also influence its activity. She proposed a dissertation project exploring that possibility. Her advisors rejected the idea in favor of a different project, but Reddy kept it in the back of her head. Then, after grad school, she garnered a postdoc in the lab of Harinder Singh at the University of Chicago, an investigator who had been studying the three-dimensional positioning of genes.

Singh and a handful of other researchers had conducted studies that showed a correlation between nuclear position and gene activity: Certain genes found near the inner nuclear membrane tended to be “turned off.” Reddy wanted to go one step further, to demonstrate causality—that the nuclear periphery had the power to regulate gene activity.

So she engineered a cell that could test the idea.

She devised a way to move a gene from the interior of the nucleus to the periphery and to tether that gene to the underside of the nuclear membrane. If this transition caused an active gene to turn off, then that result would support the hypothesis.

Indeed, the experiment confirmed Singh and Reddy’s suspicion. Transporting a gene to the nuclear membrane repressed the gene.

That project, which Reddy and Singh reported in Nature in March 2008, involved only one gene. Now, with her current large-scale study, Reddy is taking a more expansive view. She plans to identify all of the contact points between the genome and the nuclear membrane in two types of mouse cells, B cells and fibroblasts, and compare those results to a gene activity map, which shows each gene’s level of activity.

Reddy chose B cells and fibroblasts in part because the two cell types perform strikingly different roles. Such differences could stem from epigenetic mechanisms involving nuclear architecture. In fibroblasts, genes involved in specialized immune functions might be found tucked away in a “turned off” state beneath the nuclear membrane. Her initial results are supporting this hypothesis.

She may be exploring a new area of epigenetics, but she is starting to find colleagues who have found suggestions in their own experiments that “location matters” in gene expression. Professor of Biological Chemistry Barbara Sollner-Webb, for example, has observed that when she transfects cells with the circular DNA molecules known as plasmids, the plasmids go to different locations in the nucleus. Their final destination seems to depend on special “zip codes” encoded in the plasmid’s DNA.

Another investigator, professor of physiology Roger Reeves, who studies Down syndrome, or Trisomy 21, is interested in understanding where in the nucleus the third, or extra, chromosome that occurs in the syndrome resides; the characteristics of Down syndrome might result, in part, from this chromosome’s spatial location. Both Sollner-Webb and Reeves are planning collaborations with Reddy.

Reddy is intrigued by a raft of other scientific questions. One is how genes arrive at their destined contact regions along the nuclear membrane. The process does not appear to occur randomly, says Reddy. She suspects that genes are encoded with special addresses corresponding to different positions on the inner nuclear membrane, the way a letter carries a zip code that indicates its final destination. Another question is what happens when the normal association between a gene and nuclear membrane is perturbed.

“We’re really at the precipice of understanding all of this,” she says.

--Melissa Hendricks

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