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Yamini Dalal, Ph.D

Laboratory of Receptor Biology and Gene Expression Head, Chromatin Structure and Epigenetic Mechanisms Investigator National Cancer Institute Building 41, Room D702 41 Library Drive Bethesda, MD 20892 Phone:   301-496-6202 Fax:   Fax Number not listed E-Mail:   dalaly@mail.nih.gov Link: Other Homepage

Biography

Dr. Yamini Dalal was born and raised in Bombay, India. She became interested in chromosome structure and epigenetic gene regulation during her Baccalaureate years at St. Xavier's College, where she graduated with a double major in Biochemistry and Life Sciences in 1995. She moved to the United States for her post-graduate work, focusing on understanding how DNA sequence motifs can shape the chromatin structure. In Arnold Stein's laboratory at Purdue University, she studied nucleosome positioning in vivo in mouse. The nucleosome positioning could be predicted by in silico, using computational modeling and recapitulated in vitro, using just purified histones and DNA. She also studied how linker histone H1 could influence nucleosome positioning and chromatin folding in vitro and in vivo. She received her Ph.D. from Purdue University in 2003.

Histone variants were the next natural step in teasing out how intrinsic variability in the chromatin fiber can encode a diversity of biological functions. To study this aspect of chromatin structure, Yamini moved to Seattle to work with Dr. Steven Henikoff at the Fred Hutchinson Cancer Research Center from 2003-2007. Using a range of biochemical analyses ranging from nuclease assays to electron and atomic force microscopy, she and colleagues uncovered that the centromere-specific histone variant makes a strikingly unusual nucleosome, features of which are reminiscent of the nucleosomes found in the archaebacteria. This work will dominate future research aims of the laboratory.

Research

The human genome project and other sequencing projects have provided biologists with a vast amount of information about DNA sequences that comprise various organisms. In eukaryotes, the genome is intimately coupled with highly conserved canonical histone proteins, which make up half the nuclear content. Histones H2a,H2b,H3, H4 form pseudo-symmetrical bead-like units called nucleosomes around which 147bp DNA is wrapped. These repeating units package the entirety of the genome, with spacing between individual nucleosomes dictated by DNA sequence as well as linker histone H1. Furthermore, in regions of functional importance, the histone variants H3.3, CenH3, H2A.X, macro H2a, H2A.Z are often found to substitute their canonical counterparts within the nucleosome. The histone variants dramatically alter the structure and dynamics of the local chromatin fiber resulting in epigenetic control of functions ranging from promoter accessibility to centromere identity.

We focus on centromeres to elucidate the relationship between histone variants, chromatin fiber structure, assembly/disassembly dynamics and biological function. Centromeres are the visually striking central constriction seen eukaryotic mitotic chromosomes, and are the site for microtubule attachment. The centromeric chromatin fiber presents a near-perfect model for studying epigenetic control, because no single DNA sequence is deemed necessary for formation, specification, maintenance or function of the centromere. Rather, the key element appears to be the histone H3 variant CenH3, and its exclusive enrichment at a location within the genome marks that region to be the centromere in thousands upon thousands of cell generations. How this remarkable feat is accomplished remains a central question in biology. We have uncovered features of the individual CenH3-nucleosome that are strikingly different from those seen in canonical nucleosomes in vivo, in fly. These structural differences may determine the accessibility of the centromeric chromatin fiber during the cell cycle so that kinetochore proteins can distinguish CenH3 nucleosomes from canonical, in order to form the fully functional centromere at mitosis. Furthermore, the unusual tetrameric organization of the CenH3 nucleosome at interphase may indicate an ancient evolutionary connection to the ancestral tetrameric nucleosomes such as those found in the archaebacteria.

Current goals of the lab are to elucidate how CenH3 nucleosomal structural variation alters through the cell cycle, how assembly and disassembly kinetics influence the centromeric chromatin fiber accessibility and uniformity, how the global chromatin fiber's three-dimensional arrangement is altered when the individual nucleosomes that make up the fiber are replaced by CenH3 variants as in cancer cells, and whether the distinctive features we observe in fly are conserved in other species such as mammals, plants or worms. In collaboration with Stuart Lindsay at Arizona State University, we are also pursuing new technologies that would allow single molecule recognition and imaging of native chromatin using applications of atomic force microscopy.

We are currently recruiting for senior and junior postdoctoral positions. Please visit the other LRBGE homepage for more information.

This page was last updated on 10/9/2008.