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But Alt wanted to know how the cell ensured the order in which the genes were combined. The hint came when he was looking at the DNA between D and V gene segments. He noticed a stretch of DNA that’s found elsewhere in the genome and is known to regulate DNA transcription. A protein called CTCF that attaches to certain DNA sequences to regulate gene expression can bind to the region. It folds the surrounding DNA into loops.
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DNA Transcription
Learn about the process of copying DNA into messenger RNA (mRNA).
 
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Alt wanted to know the role of the so-called CTCF-binding element in controlling the assembly of antibody genes. So he mutated the binding element, with drastic results.
“We saw a very unordered pattern of antibody gene generation,” says Alt. Segments from the V genes joined with Ds before the Js were tacked on. And only a few of the possible V segments were used, leading to fewer unique antibody possibilities. Moreover, cells lost the ability to ensure production of only one antibody at a time. Both specificity and diversity were obliterated. His group, led by postdoctoral fellow Chunguang Guo, published the observations September 11, 2011, in Nature.
“This site impacts every regulatory process that we’ve been studying for 30 years,” Alt says of the CTCF.
The CTCF protein is normally bound to the CTCF-binding site during development. Alt’s team discovered that the antibody gene forms a number of loops that require the bound protein. Transcription proteins—which travel along DNA and use it as a blueprint for RNA strands—get stuck between the D and V segments because of these loops, Alt thinks. The arrangement allows developing cells to produce antibodies with only the D and J regions; the V segment is added later.
“Genes have incredibly complex three-dimensional organization,” Alt says. “And we’re learning that all of biology depends on that organization.”
Alt’s next task is to uncover the other proteins responsible for controlling the CTCF site. Now that
he’s found a master control site that keeps the V from being added to antibodies too early, he wants to know what signals the cell to finally add the V segment. Stay tuned. 
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