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Shelley
L. Berger
Hilary Koprowski Professor
Genetics
and Gene Regulation Program
Address
The Wistar Institute
3601 Spruce Street
Philadelphia, PA 19104-4265
Office tel.: 215 898 3922
Lab tel.: 215 898 3975
Fax:215 898 0663
E-mail:berger@wistar.upenn.edu
Link(s)
Dr
Berger at the Wistar Institute
Education
University of Michigan, B.S.
(Biology),1977
Univeristy of
Michigan, Ph.D. (Cell & Molecular Biology),1987
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Research
Interests
- Chromatin structure and function in gene
regulation
- Post-translational modifications of transcription
factors and histones
- Genetic, biochemical and structural analysis
of chromatin in S. cerevisiae and human cells
- Role of interrelated factor/histone modifications
in cancer and viral infection
Key words: transcriptional regulation,
chromatin, histone modifications, acetylation
Search PubMed for articles
Description
of Research
Role of covalent modifications of histones
and transcription factors in gene regulation
Our research focuses on gene regulation in a chromatin context,
using S. cerevisiae, human cells and herpes simplex virus
(HSV-1) as model systems. We are also interested in alterations
of chromatin underlying oncogenic states in humans. Beginning
with a focus on histone acetylation in gene activation, new
histone modifications and patterns of modifications have been
identified that underlie the active state of genes. One pattern
on histone H3 that has been extensively examined is initial
phosphorylation on Ser-10, which stimulates acetylation on
Lys-14. It is thought that this initial pattern is representative
of an enormous variety of histone modification patterns (a
“histone code”) that specifies different genomic
processes, including transcriptional activation and repression,
replication, mitotic chromosome condensation, recombination
and DNA repair. The lab studies a wide range of histone modifications,
including acetylation, phosphorylation and ubiquitylation,
and their dynamic interplay.
These basic mechanistic studies form the background for understanding
cancer and other other human diseases. Thus, a second focus
is on covalent modifications of transcription factors and
their relationship to cancer. The lab has identified novel
acetylation sites in the tumor suppressor and transcriptional
activator p53, and have demonstrated a direct relationship
to histone modifications. Our emerging view is that there
is a modification cascade, whereby a “factor code”
of modifications leads to a related “histone code”.
New areas of interest in cancer are abnormal changes in the
histone code from the benign to metastatic states in breast
and other solid tumors. Our objective is to determine whether
these changes are central to the metastatic phenotype, and
if so, could be inhibited as treatment.
Finally, we also study the DNA tumor virus HSV-1.
Recently we have observed that HSV-1 is chromatinized during
infection, which is a novel finding, and that the virus uses
a typical histone code for activating its genes. We are currently
investigating whether establishing this code is critical for
infection, and if so, could emerge as a potential point of
theraputic intervention in herpes infections including encephalitis.
Recent
Publications
Zhou J and Berger SL (2004) Good fences make
good neighbors; barrier elements and genomic regulation. Mol
Cell, 16(4):500.
Ingvarsdottir K, Krogan NJ, Emre NC, Wyce A,
Thompson NJ, Emili A, Hughes TR, Greenblatt JF, Berger SL
(2005) H2B ubiquitin protease Ubp8 and Sgf11 constitute a
discrete functional module within the Saccharomyces cerevisiae
SAGA complex. Mol. Cell Biol. 25(3):1162.
Lo W-S, Gamache ER, Henry KW, Yang D, Pillus
L, Berger SL (2005) Histone H3 phosphorylation can promote
TBP recruitment through distinct promoter-specific mechanisms.
EMBO J. 24(5):997.
Emre NCT, Ingvarsdottir K, Wyce A, Wood A,
Krogan NJ, Henry KW, Li K, Marmorstein R, Greenblatt JF, Shilatifard
A and Berger SL (2005) Maintenance of low histone ubiquitylation
by Ubp10 correlates with telomere-proximal Sir2 association
and gene silencing. Mol Cell, 17(4), 585.
Nathan D, Ingvarsdottir K, Sterner DE, Bylebyl
GR, Dorsey JA, Meluh PB, Lane WS, Johnson ES, Berger SL (2006)
Histone sumoylation represses transcription and shows dynamic
interplay with histone acetylation in Saccharomyces cerevisiae.
Genes & Devel, 20(8):966.
Lab
Rotation
Projects
- Investigation of novel histone covalent modifications
(phosphorylation, ubiquitylation, sumoylation and methylation
sites) in yeast, mammals and HSV-1. Methods: mutagenesis,
reverse genetics, chromatin immunoprecipitation (ChIP assay)
and phenotyping (includes transcription, teleomeric gene
silencing, DNA repair, sporulation, and others).
- Testing novel interactions between histone
modifications and chromatin protein domains. Methods: biochemical
binding assays in vivo, bacterial expression of proteins,
cloning).
- Investigation of role of histone modifications
in p53 pathways and viral HSV-1 infection and latency pathways
in mammalian cells. Methods: mammalian cell transfection
and RNAi, viral infection in cells and mice, ChIP assays,
RNA analysis.
- Lab
personnel:
- Anastasia Wyce (5th year), graduate student
Kristin Ingvarsdottir (4th year), graduate student
Thanuja Krishnamoorthy, associate staff scientist
Wendy Walter, postdoctoral fellow
Brandon Placek, postdoctoral fellow
Jing Huang, postdoctoral fellow
David Bungard, postdoctoral fellow
Lyndi Rice, postdoctoral fellow
Weiwei Dang, postdoctoral fellow
Jean Dorsey, lab manager
Mary Swyer, technician
William E. Alston, research services coordinator
last updated 6/2006
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