Loss of Insulator Activity by Paired Su(Hw) Chromatin Insulators

GENEVA , Switzerland, January 19, 2001 Insulators are genomic regulatory elements that block the effects of chromatin structures, repressive elements or stimulatory elements that lie on one side of the insulator from influencing the proper functioning of a gene that lies on the other side of the insulator. In this sense, an insulator was thought to act like a wall, protecting a gene from inappropriate effects of other flanking genes. This is important to insure that when a particular gene is activated, it does not also cause inappropriate activation of neighboring genes; or, conversely, repressive elements that turn off a particular gene are prevented by the insulator from turning off other neighboring genes.

In a paper published in a recent issue of Science (2001 ; 291:495-498.), in collaboration with the laboratory of Dr Pavel Georgiev of the Russian Academy of Sciences, University of Geneva s Prof. Vincenzo Pirrota and his team reported that an insulator has surprising and unexpected property. While one copy of the insulator acts as a block, placing two copies of the insulator side by side neutralizes the blocking effect. This paradoxical effect indicates that the insulator does not act as a passive wall but its function depends on interactions with other insulators or regulatory elements in a genomic domain. Current experiments suggest that protein complexes bound to one insulator can interact with protein complexes bound to the nearby insulator.

Several kinds of insulator elements have now been discovered and the number continues to increase. In the human genome insulators have been found, among other places, in the control region of certain genes that are genetically

imprinted. In genetically imprinted genes, the copy of the gene inherited from the mother is expressed differently from the copy of the gene that is inherited from the father. The insulin-like growth factor 2, important for fetal growth, is carefully regulated so that the maternal copy is silent and only the paternal copy is expressed. Failure to turn off the maternal copy results in fetal overgrowth and is associated with the genetic disorder known as Beckwith-Wiedeman Syndrome. An insulator element placed between activator sequences and the Igf2 gene is responsible for keeping the maternal copy silent.

Insulator elements are being used in genomic research as a way to protect transgenes from being inactivated by inactive chromatin surrounding the genomic insertion site. In the future, insulators might find similar applications in gene therapy or in the construction of transgenic organisms.