Shigeru Sakonju, Ph.D.
Associate Professor

Contribution to Society

Many biological processes of the fruit fly are similar to those in higher organisms, including the mouse and humans. Drosophila homeotic genes seem to function in much the same way in the mouse; thus they probably act similarly in humans. Homologous genes from many other Drosophila regulatory genes have been identified in mammals. Many oncogenes are related to genes that play important roles during the development of Drosophila. These similarities have and will continue to shed light on many medical problems that face our society.

Research Summary

We study the regulation of homeotic gene expression in the fruit fly Drosophila melanogaster. Homeotic genes are master regulatory genes, conserved from flies to humans, that specify the identities of body segments. Each homeotic gene is expressed in a unique body domain along the body axis and directs cells to follow appropriate developmental pathways for their positions. If it is misexpressed outside of its normal domain, it transforms the misexpressing body segments to look like another segment. These sometimes specutacular homeotic transformations are not only amusing to look at, but also essential for understanding how homeotic genes are regulated and how they function. Understanding these, in turn, gives us insights into how the body of higher organisms, including humans, is patterned.

The current focus of our lab is to understand how silencing of homeotic genes is maintained. Maintenance of silencing relies on the Polycomb group proteins which appear to form some chromatin structure that prevents genes from becoming activated. Recently we have investigated how these proteins recognize their appropriate targets. DNA regulatory elements called the Polycomb Response Elements serve as targets for the Polycomb group proteins. By molecularly dissecting a PRE element from the homeotic gene Abd-B, we have identified two proteins that bind to specific sequences in this element. Their binding to the PRE is essential for Polycomb group proteins to exert their silencing effect. How do these proteins recruit the Polycomb proteins? It's still not clear, but we are investigating various possibilities. One possibility is that they directly recruit Polycomb group proteins. Another possibility is that they first recruit histone deacetylase complexes to the PRE, and it is deacetylated histones that are recognized by Polycomb group proteins. Yet another possibility is that the PRE binding proteins physically alter the location of nucleosomes over the PRE. We are investigating these and other models using genetic, molecular and biochemical approaches.
Another aspect of PREs we are studying is their ability to silence promoters located on another chromosome. The molecular basis of PREs to act in trans is not understood. Similarly to this trans-silencing by PREs, there is an element within the regulatory region of Abd-B that can activate its target promoter in trans, even when the target is located on a different chromosome. How are these amazing feats accomplished? We are using a genetic approach to identify the molecular components of these processes.

Recent Publications

Busturia A, Lloyd A, Bejarano F, Zavortink M, Xin Hua, and Sakonju S (2001) The MPC silencer of the Drosophila Abd-B gene requires both Pleiohomeotic and GAGA factor binding sites for the maintenance of repression. Development 128(11):2163-73.

Busturia A and Sakonju S (1999) Epigenetics, Silencer, Epistasis. In Encyclopedia of Molecular Biology. (Ed. T. Creighton), Wiley and Sons.

Busturia A, Wightman CD and Sakonju S (1997)
A silencer is required for maintenance of transcriptional repression throughout Drosophila development. Development 124(21):4343-4350.