[Research Interests] [Representative Publications] [Lab Members] RESEARCH INTERESTSThe goal of our research is to understand epigenetic mechanisms controlling the expression of eukaryotic genes. The main focus of our lab is to study the organization of the chromatin fiber within the eukaryotic nucleus and the mechanisms controlling this organization. We are also interested in the role of the primary structure of the chromatin fiber, as determined by histone tail modification, in the regulation of transcription. Nuclear organization and gene expression The
eukaryotic genome is highly compacted within the nucleus. In order to
properly regulate the expression of genes in a tissue and
temporal-specific manner, the genome is thought to be organized into
structural chromatin domains that promote the autonomy of gene
activity. Chromatin insulators or boundary elements are thought to be
responsible for establishing such domains. Insulators are
operationally defined by two properties – they are able to interfere
with
 enhancer-promoter communication and they shield integrated transgenes
from effects of the surrounding chromatin. Insulators have now been
characterized in a variety of species, suggesting their importance in
the global regulation of gene expression. Because
insulators act by establishing higher order domains of chromatin
structure, their properties and mechanisms of action have been
difficult to analyze. We are using Drosophila as a model system
in which to study the function of an insulator first identified in the gypsy retrovirus. We have identified several different proteins
that form a complex with insulator DNA and we are in the process of
analyzing their function. Results from this analysis have allowed us
to propose a model in which proteins bound to insulators help
organize the chromatin fiber within the nucleus by attaching the DNA to a subnuclear structure.
This organization seems to be essential for the proper regulation of eukaryotic genes. Additional information on this
topic can be found in the webpage of the Corces Lab.Histone modification and transcription The basic organizational unit of the chromatin fiber, the nucleosome,
consists of the DNA molecule wound around an octamer comprised of the core histones H2A, H2B, H3
and H4. Covalent modifications of the histone N-terminal tails are proposed to act as
signals from the DNA to the cellular machinery for various processes including transcription,
chromosomal condensation and mitotic segregation. We have used the heat shock response in Drosophila as a model
system to study the role of histone H3 phosphorylation in transcriptional control. During a heat
shock, transcription and translation of most normally expressed
cellular gene products in Drosophila cells ceases while expression
of the heat shock genes is rapidly induced. Results from our experiments indicate that global level of phosphorylated H3 decreased REPRESENTATIVE PUBLICATIONSDorman E.R., Bushey A.M., and Corces, V. G. 2007. The role of insulator elements in large-scale chromatin structure in interphase. Semin Cell Dev Biol. 18:682-90. Gerasimova, T. E. Lei, A. Bushey, A., and V. Corces. 2007. Coordinated control of dCTCF and gypsy chromatin insulators in Drosophila. Molecular Cell. (in press). Ivaldi, M.S., Karam, C.S., Corces V. G. 2007. Phosphorylation of histone H3 at Ser10 facilitates RNA polymerase II release from promoter-proximal pausing in Drosophila. 21:2818-31. Genes Dev. (in press).
Lei, E. P. and Corces, V. G. 2006. The RNAi machinery influences the nuclear organization
of a chromatin insulator.
Nat. Genet., in press. Lab MembersResearch Associates Research Technician
Undergraduate Students Jason Feinberg Gabe Ferguson David Tomich Katie Villa |
dramatically
during a heat shock, with an observed increase in H3 phosphorylation at the heat shock loci. These
experiments suggest that H3 phosphorylation has an important role in the activation of transcription.
We have extended these results to other genes, and conclude that H3
phosphorylation is an essential step during the promoter clearance
process in the transcription of all Drosophila genes. The levels
of phosphorylated histone H3 are maintained by a balance between the
activities of the JIL-1 kinase and the PP2A protein phosphatase.
We are currently exploring the mechanisms by which the activity of these
two enzymes is regulated to control chromatin structure and
transcription.
Additional information on this topic can be found in the webpage of
the