Professor of MCD Biology
B.S., N. Wadia College
M.S., University of Poona (India)
Ph.D., Cambridge University
1989-1993: Postdoctorate, University of California, San Diego;
1993: Postdoctorate, University of California, Berkeley
Chromatin in the eukaryotic nucleus can be conceived as a three dimensional mosaic of physically and functionally distinct domains suspended in the nuclear milieu. How this physical and functional organization influences gene regulation is one of the most intriguing questions in modern biology.
Research in our laboratory is devoted to understanding the mechanism by which the genome is partitioned into structural and functional units. We employ molecular and genetic analysis coupled with biochemical experiments to explore the issues of genome organization. We are presently working on 1) the architecture of the silenced chromatin domains and 2) the mechanism by which chromatin domains are delimited.
Eukaryotic chromosomes are organized into discrete active and silenced domains de-limited by insulator elements. We are interested in understanding the mechanism by which silenced chromatin domains are restricted to specific regions along the DNA fiber. We have been characterizing a specific insulator element that mediates insulator function at a silenced locus in yeast. We have shown that proteins bind the insulator and function to block the spread of silencing in conjunction with chromatin remodeling and modifying complexes. Our data suggest that multiple overlapping mechanisms are involved to delimit silenced and active domains in vivo. We are very interested in determining the precise steps by which these proteins function to form a boundary and block the spread of silencing. In pursuit of this goal we are currently performing genome wide screens for proteins and mutants that affect the spread of silencing coupled with precise quantitaive mapping of the distribution of various proteins at the insulator elements.
We are simultaneously analyzing the native structure of the silenced domain in the nucleus and find that the domain is packaged into a chromatin loop stabilized by repressor proteins. We are very interested in determining the elements necessary for the formation of these chromatin loops and their relationship to previously identified elements such as promoters, silencers and insulator elements. Future goals involve the reconstitution of the silenced chromatin domain using purified Sir protein complexes and histones. These studies will provide an important index of our current understanding of transcriptional silencing depending on whether or not it is possible to reconstitute the silenced state.
Understanding how the nucleus is organized is important in fully understanding the mechanisms by which basic processes such as transcription occur and should help us better manipulate these processes for benefit in research and medicine.
Please follow this link to find the lab's publications in the National Library of Medicine's PubMed database.