Molecular partners required for appropriate neuronal gene repression

In their efforts to understand the complex biology of life, scientists often seek to isolate individual elements of the puzzle for study, to break the problem down to a more manageable size. Single genes and molecules are closely analyzed to better understand their specific interactions with other single entities within larger systems.

Sometimes, however, this approach misses important aspects of biology that depend on higher levels of organization. Sometimes putting a few of the pieces back together again reveals new information that would otherwise remain obscured.

A new study by researchers at The Wistar Institute demonstrates this point. Aiming for insights into the intricate biochemistry governing gene regulation, the scientists investigated the activity of a recently discovered enzyme pivotally involved in this process. A report on their findings, which may have long-term implications for treating depression and other psychiatric disorders, was published online by Nature today.

The enzyme’s function is to remove methyl groups from histones to modify them in ways that trigger gene repression. Eight histones comprise a nucleosome, and long strings of nucleosomes coil in turn into chromatin, the basic material of chromosomes. In the body’s scheme for safely storing genes away until needed, DNA is tightly looped around the histones, kept secure by enzymes similar to the one studied by the Wistar team until made accessible by the activity of related enzymes responsible for gene expression.

What the scientists found was that while the enzyme was able to demethylate its target histone when the pair was in isolation, it was unable to do so when the histone was placed in the more complex and realistic setting of a nucleosome. They then coupled the enzyme with other molecules with which it is known to complex to discover that one of them enabled the enzyme to act upon the histone and is, in fact, required for the enzyme’s effectiveness in vivo.

“The real field of action for these enzymes is chromatin, not the histones,” says Ramin Shiekhattar, Ph.D., an associate professor at Wistar and senior author on the Nature study. “In our experiments, the enzyme alone was active with histones, but when we tested it on chromatin, we saw something very interesting – the enzyme was completely inactive on nucleosomes. On the other hand, the complex containing the enzyme worked well. The goal then became to determine what in the complex conferred this capability on the enzyme.”

The complex, known as BHC, contains five components, including the enzyme studied by Shiekhattar and his coworkers, referred to either as BHC110 or LSD1. Further experiments by the team revealed that the enzyme requires the presence of another member of the complex called CoREST to act on nucleosomes.

Intriguingly, the enzyme in question, which helps to appropriately repress neuronal genes in non-neuronal cells and tissues, fits into the same extended enzyme family that includes monoamine oxidases, psychoactive enzymes that oxidize dopamine and norepinephrin. Inhibitors of these enzymes have long been used to treat depression, certain other psychiatric and emotional disorders, and Parkinson’s disease. A clearer understanding of this particular gene-repression system might suggest new approaches to treatments for an array of psychiatric conditions.

The lead author on the Nature study is Min Gyu Lee. Christopher Wynder and Neil Cooch are coauthors. Senior author Shiekhattar is an associate professor in two programs at Wistar, the gene expression and regulation program and molecular and cellular oncogenesis program. Support for the research was provided by the National Institutes of Health.