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Archives of Industrial Biotechnology | Volume 2
May 14-15, 2018 | Montreal, Canada
World Yeast Congress
Y
east cells subjected to many different stresses elicit an
acute transcriptional stress response mediated by the
Msn2 transcription factor, which alters expression of both a
stress specific cohort of genes as well as a common cohort of
genes that changes expression in a stereotypic fashion upon
exposure to any of a wide variety of stresses. We have shown by
dynamic single cell analysis that stresses regulate Msn2 activity
through cytoplasmic to nuclear relocalization but do so in an
unusual way: stresses induce increased frequency of bursts
of short-lived, recurrent periods of Msn2 nuclear localization
with different stresses eliciting different patterns of bursts.
Moreover, genetically identical cells subjected to an identical
stress can behave quite differently. We have proposed that this
idiosyncratic behavior allows populations of cells to “hedge
their bet” as to what will be the optimal strategy for surviving
ensuing stress. We have used computational modeling and
single cell analysis to determine that bursting is a consequence
of the noise in the stress signaling pathways, amplified by the
small number of Msn2 molecules in the cell. Moreover, we
have applied genome wide chromatin immunoprecipitation
and nucleosome profiling to address how different stresses
determine where Msn2 binds under a particularly stressful
condition and thus what genes are regulated by that stress
and how that binding affects and is affected, by nucleosome
positioning and other transcription factor binding. These
results provide an
in vivo
validation of indirect cooperativity
of transcription factor binding, mediated by partial unwinding
of nucleosomes by one transcription factor to allow access for
a second transcription factor to a previously occluded binding
site. Finally, we have addressed the “bet hedging” hypothesis
by showing that persistence of the Msn2-mediated stress
response yields cell growth arrest and have identified the
targets responsible for that growth arrest. We have applied
experimental evolution paradigms to address the relative
fitness of cells exhibiting stochastic stress response versus those
with a uniform response. In short, our results indicate that the
stress response is complex and that complexity is critical for cell
survival.
Speaker Biography
JamesRBroach isadistinguished Professorand Chair ofthedepartmentofBiochemistry
and Molecular Biology at Penn State College of Medicine, Director of the Institute for
Personalized Medicine. He was Professor of molecular biology at Princeton University
from 1984-2012, where he served as an Associate Director of the Lewis Sigler Institute
for Integrative Genomics and Co-Director of the Center for Computational Biology. He
has served as Chair of the Genomics, Computational Biology and Technology Study
Section at NIH as well as Chair of Numerous Special Emphasis Genomics Panels. He was
Co-Founder and Director of Research for Cadus Pharmaceuticals from 1992 to 2000. He
is a Fellow of the American Academy of Microbiology and of the American Association
for the Advancement of Science. He has published more than 175 articles in the area
of Molecular Biology and Genomics and holds a number of patents in Drug Discovery
Technologies.
e:
jbroach@pennstatehealth.psu.eduJames R Broach
Penn State College of Medicine, USA
Coping with stress: Lessons from yeast