Molecular Partners Required For Appropriate Neuronal Gene Repression

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

A new study by researchers at The Wistar Institute demonstratesthis point. Aiming for insights into the intricate biochemistrygoverning gene regulation, the scientists investigated the activity ofa recently discovered enzyme pivotally involved in this process. Areport on their findings, which may have long-term implications fortreating depression and other psychiatric disorders, was publishedonline by Nature today.

The enzyme's function is to remove methyl groups from histonesto modify them in ways that trigger gene repression. Eight histonescomprise a nucleosome, and long strings of nucleosomes coil in turninto chromatin, the basic material of chromosomes. In the body's schemefor safely storing genes away until needed, DNA is tightly loopedaround the histones, kept secure by enzymes similar to the one studiedby the Wistar team until made accessible by the activity of relatedenzymes responsible for gene expression.

What the scientists found was that while the enzyme was able todemethylate its target histone when the pair was in isolation, it wasunable to do so when the histone was placed in the more complex andrealistic setting of a nucleosome. They then coupled the enzyme withother molecules with which it is known to complex to discover that oneof 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, notthe histones," says Ramin Shiekhattar, Ph.D., an associate professor atWistar and senior author on the Nature study. "In our experiments, theenzyme alone was active with histones, but when we tested it onchromatin, we saw something very interesting -- the enzyme wascompletely inactive on nucleosomes. On the other hand, the complexcontaining the enzyme worked well. The goal then became to determinewhat in the complex conferred this capability on the enzyme."

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

Intriguingly, the enzyme in question, which helps toappropriately repress neuronal genes in non-neuronal cells and tissues,fits into the same extended enzyme family that includes monoamineoxidases, 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'sdisease. A clearer understanding of this particular gene-repressionsystem might suggest new approaches to treatments for an array ofpsychiatric conditions.

The lead author on the Nature study is Min Gyu Lee. ChristopherWynder and Neil Cooch are coauthors. Senior author Shiekhattar is anassociate professor in two programs at Wistar, the gene expression andregulation program and molecular and cellular oncogenesis program.Support for the research was provided by the National Institutes ofHealth.

The Wistar Institute is an independent nonprofit biomedical researchinstitution dedicated to discovering the causes and cures for majordiseases, including cancer, cardiovascular disease, autoimmunedisorders, and infectious diseases. Founded in 1892 as the firstinstitution of its kind in the nation, The Wistar Institute today is aNational Cancer Institute-designated Cancer Center focused on basic andtranslational research. Discoveries at Wistar have led to thedevelopment of vaccines for such diseases as rabies and rubella, theidentification of genes associated with breast, lung, and prostatecancer, and the development of monoclonal antibodies and othersignificant research technologies and tools. News releases from TheWistar Institute are available to reporters by direct e-mail uponrequest.