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
The primary DNA sequence of an organism determines their unique genetic makeup. DNA in the eukaryotic nucleus associates with several structural and enzymatic proteins to form chromatin. This packaging affects the ability of genes to be transcribed into RNA and only a subset of genes undergo active transcription in any given cell at any particular time. Specific gene transcription is achieved by enhancer bound transcription factors that recruit specific chromatin remodeling and modifying enzymes to form open euchromatin. Conversely, silencer bound factors recruit distinct enzyme machineries and repressor proteins to modify chromatin resulting in the formation of condensed heterochromatin that silences genes.
Chromosomes occupy specific territories in the eukaryotic nucleus and these territories are further subdivided into accessible euchromatic and inaccessible heterochromatic domains. Regulatory elements such as enhancers and silencers thus function within the context of these chromatin domains while insulators partition these active and inactive domains.
Given how central gene regulation is to proper growth, differentiation and development, understanding the complex interplay between chromatin domains, chromosome structure and gene activity is the primary focus of research in my laboratory.
Role of DNA repair proteins in nuclear organization
Heterochromatin domains interact with other silenced domains at the nuclear periphery while regulatory elements of active genes often cluster together at transcription factories. We are currently identifying and characterizing the proteins and mechanisms involved in the three-dimensional organization of chromatin domains in the eukaryotic nucleus. We recently showed that heterochromatin clustering is disrupted in various mutant proteins involved in gene silencing as well as proteins necessary for double strand break repair. We are now focused on determining the mechanism by which DNA repair proteins function in nuclear organization using various molecular genetic approaches.
Role of tDNAs in gene regulation in yeast and humans:
The canonical function of tDNAs is to generate tRNAs for translation of mRNAs. Specific transcription factors required for transcription of tDNAs bind these genes and recruit several chromatin remodeling and modifying enzymes which generates a unique chromatin state at these genes allowing their transcription. The location of tDNAs along the chromosome affects chromosome structure, which in turn modulates expression of neighboring genes.
We have shown that tDNAs function as gene insulators; they block the spread of heterochromatin as well as prevent enhancers from activating promoters when juxtaposed between these elements. We are currently dissecting the role of various transcription factors and co-factors in tDNA-mediated gene insulation, transcription control and chromatin structure in human and yeast cells to gain a better understanding of the interplay between RNA pol II specific transcription activators and the RNA pol III machinery present at tDNAs during gene regulation.
Role of tDNAs in chromosome organization
Various chromosome structural proteins such as condensins and repairsins also localize to tDNAs whereas tDNAs are necessary for loading cohesins onto chromosomes. It has therefore been proposed that tDNAs function to organize chromosomes via these chromosomal structural proteins. We are focused on testing the role of tDNAs in chromosome organization. We have generated a novel resource where we have deleted every tDNA on a chromosome in yeast and are characterizing the effects of tDNA loss on chromosome organization and dynamics during the cell cycle using fluorescence microscopy and genome-wide mapping of various proteins.
Please follow this link to find the lab's publications in the National Library of Medicine's PubMed database.