Scientists Establish Link Between DNA Replication and Gene Expression

CAMBRIDGE, Mass. — Faced with an infection, the human body’s first line of defense is to produce millions of antibodies to neutralize the infection. Orchestrating this defense is the human immune cell called the B cell, which has the amazing ability to produce an army of antibodies, each a replica of the other and each tailor made for a specific infectious agent. In fact, maternal and paternal copies of genes can produce antibodies that are not exact replicas, so the B cell must silence one of them to avoid disorders of the immune system. But how a B cell pulls off this stunt has been a mystery.

Now, a study by researchers in Andrew Chess’s lab at the Whitehead Institute and Yehudit Bergman’s lab at Hebrew University, sheds light on this process, called allelic exclusion. For the first time, the researchers found that during B cell division one set of genes—either from the mother or the father—is copied early and these are the genes that go on to produce a particular antibody. These results, published in the November 8 issue of Nature, represent a significant step in understanding the mechanisms underlying this critical cellular process.

"For decades scientists have known that allelic exclusion assures that only one type of antibody is produced by each B cell. Over the years, many studies focused on how either the maternal or paternal gene is silenced. But this is the first study to determine how the initial choice is made between two essentially identical copies of a gene," says Chess. "These recent results indicate that the two copies aren’t identical to the cell in that one replicates early. Once a gene replicates early that particular gene will go through a complex process of rearrangement that contributes to a unique antibody."

"Interestingly, once a cell picks a gene to replicate early, all of the cell’s progeny will pick the same copy of the gene to be replicated early, which means replication timing is a heritable quality," adds Nandita Singh, postdoctoral associate in the Chess lab and a lead author on the paper.

Using a process called fluorescence in situ hybridization, or FISH, the researchers were able to visualize the timing of DNA replication within the cell’s nucleus. For most genes, both copies will be replicated simultaneously during cell division. The researchers show that in B cells this isn’t the case and only the early replicating gene is expressed in the mature cell. When two genes are not copied simultaneously, they go through what is referred to as "asynchronous replication."

"Asynchronous replication may be a way for cells in early development to distinguish between maternal and paternal genes in the rare cases where one copy of a gene must be turned off later in development," says Chess. Most genes are inherited in pairs—one copy from the mother and one from the father—and in most cases both produce proteins. In some notable exceptions, including antibody production, one copy is randomly turned off so the cell can function properly. This is the case with X inactivation, when one of two X chromosomes in females is randomly silenced during development. Previously, the Chess lab showed that olfactory receptor gene clusters involved in smell are also regulated by asynchronous replication.