Newly identified molecules contribute to normal silencing of most human genes

Connections seen to X-linked mental retardation and some forms of leukemia

Most of the time, most of the estimated 35,000 genes in the human genome are silent, securely stored away in the tightly coiled structure of chromatin, which makes up chromosomes. Inside chromatin, the DNA is wound around small proteins called histones, making it unavailable to the cellular machinery that would otherwise read its coded genetic information. Specific cell and tissue types are characterized by the carefully controlled activation of selected sets of signature genes.

Now, a team of researchers at The Wistar Institute reports discovery of a family of molecular complexes involved in the repression of extensive sets of tissue-specific genes throughout the body. Additionally, one member of the family involved in repressing brain-specific genes in other types of tissues has been found to include a gene thought to be responsible for X-linked mental retardation when mutated. Other components of these complexes have been associated with certain forms of leukemia.

The new study appears in the current issue of the Journal of Biological Chemistry.

“One of the mysteries of gene expression is how different tissues in the body -heart, liver, brain – express the genes that are specific to them,” says Ramin Shiekhattar, Ph.D., senior author on the report and an associate professor at The Wistar Institute. “What really controls this? For a long time, people have been looking for the factors that activate these genes, but what we and others are learning is that the critical mechanism used to regulate entire sets of genes is actually repression.

“In some ways, it’s like driving a car. You may not realize much driving relies on braking rather than acceleration. Without the brake, you can’t control the car.”

The new findings may have relevance for understanding diseases characterized by uncontrolled or inappropriate gene activation and growth, with cancer perhaps the most significant of these.

The newly discovered molecular complexes share two core subunits and appear to operate as co-repressors with a number of tissue-specific repressor molecules to maintain the gene-silencing structure of chromatin.

One of the shared subunits is a type of enzyme, a so-called histone deacetylase, or HDAC, known to repress gene activation by modifying chromatin structure in specific ways. The second core subunit shared by these new complexes is called BHC110. This component, too, appears to be an enzyme, Shiekhattar says, although its specific activity remains to be determined.

Biochemical assays showed that BHC110 and the HDAC enzyme were both present in up to ten other unique complexes likely be involved in gene repression. Current experiments are aimed at learning more about the function of these two shared components of the complexes, and also at learning more about the components unique to each complex.

The equally contributing lead authors on the Journal of Biological Chemistry study are Mohamed-Ali Hakimi, Ph.D., and Yuanshu Dong, both at The Wistar Institute. William S. Lane at Harvard University collaborated on the study, as did Wistar professor David W. Speicher, Ph.D.

This research was supported by grants from the National Institutes of Health and the American Cancer Society.

The Wistar Institute is an independent nonprofit biomedical research institution dedicated to discovering the causes and cures for major diseases, including cancer, cardiovascular disease, autoimmune disorders, and infectious diseases. Founded in 1892 as the first institution of its kind in the nation, The Wistar Institute today is a National Cancer Institute-designated Cancer Center – one of only eight focused on basic research. Discoveries at Wistar have led to the development of vaccines for such diseases as rabies and rubella, the identification of genes associated with breast, lung, and prostate cancer, and the development of monoclonal antibodies and other significant research technologies and tools.

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