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Biological Questions

Interactions with co-inhabiting species in the environment:linking environmental and genetic systems approaches

All organisms, regardless of their complexity, live in, and rely upon diverse and interconnected communities.  Hypersaline organisms are no exception, and the diversity of species and their characteristic ecological functions are only recently being characterized in high detail.  To that end we are applying a multiscale systems approach to examine how perturbations to ecological equilibriums are reflected in the gene expression states of constituent species, and vice versa.  In doing so, we should gain an important understanding of how seemingly minute changes in cellular behavior can impact regional environments.

 

Personnel: Institute for Systems BiologyLee Pang , Kenia Whitehead, Monica Orellana, Min Pan, Amanda Pease, Aimee Desaki, David Rodriquez (Aderem Group)

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DNA Damaging Radiation

The degree of sensitivity exhibited by an organism to ultraviolet (UV) radiation is related to the number and efficiency of repair systems as well as the existence of avoidance strategies such as phototaxis or protective mechanisms such as the production of photoprotective substances. Identifying and understanding the regulation of these mechanisms at a genetic and biochemical level is a fundamental aspect to understanding the system wide response of an organism to this basic environmental factor. Halophilic archaea are ideal model organisms for this as they have the ability to not just withstand but thrive in high light environments.  We are currently investigating the system wide photoprotective response and repair mechanisms within halobacteria to learn the regulatory controls and physiologically underlying their UV tolerance.

Personnel: Institute for systems Biology — Kenia Whitehead, Min Pan

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Entrainment by day/night cycles

Most organisms living in the photosphere tune their daily patterns to the light/dark cycle.  The control of light conditions on biological systems is evident from the level of genes through populations.  Synchronizing biological processes with the light/dark cycle has been shown to improve organism fitness and provide a means for cells to “anticipate” events.  Recent results have shown that ~10% of the H. salinarum NRC-1 genome follows a pattern mediated by light/dark cycles even after the periodic light stimulus is removed. We are investigating the regulatory networks and molecular basis for synchronization and memory.

Personnel:  Institute for systems Biology — Kenia Whitehead, Min Pan
Div. of Genetics and Mutagenesis, Nat. Inst. of Health Sci., Tokyo, Japan - Kenichi Masamura
Department of Biological Sciences, Vanderbilt University  - Carl. H. Johnson, Tetsuya Mori, Lena Suzuki
Center for Genomics and Systems Biology, New York University - Richard Bonneau

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Oxygen availability

Maintaining homeostasis under fluctuating environmental oxygen concentrations is critical for the survival of all organisms.  Extreme oxidative stress or hypoxia can overwhelm cellular redox balance, resulting in diseases such as cancer.  Using a systems approach we have generated a model for the dynamic molecular information processing that occurs in response to changing oxygen concentrations. We are using this model to delineate posttranscriptional regulatory mechanisms in response to oxygen changes.

Personnel: Institute for systems Biology — Amy Schmid

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Transition Metals

Cells sustain metal ion levels within physiological limits through their selective transport, trafficking, enzymatic conversion into non- or less toxic redox states, or sequestration with ferritins and metallothioneins.  Genetic defects or environmental insults that perturb these processes can result in abnormal metal levels with severe health implications including Wilson's and Menkes diseases, and numerous hepatic and neuropsychiatric problems.  We are using a systems approach to characterize the regulatory networks responsible for coordinating metal resources inside a cell.  We are coupling the systems scale modeling efforts with smaller scale but higher resolution analysis of sub-circuits using microfluidic devices.

Personnel: Institute for Systems BiologyLee Pang (lpang) , Amy Schmid, Amardeep Kaur

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Oxidative Stress

Oxidative stress is a condition of increased reactive oxygen (ROS) that has been implicated in the physiology of many chronic diseases and aging process.  Understanding mechanisms to manage oxidative stress could prove key determinants to reduce oxidative burden, improve longevity and cure diseases. Extremophiles (organisms living in extreme environments) are routinely exposed to stress conditions that generate enormous oxidative stress.  We are using the extremophile Halobacterium salinarum to characterize the oxidative stress response and delineate associated regulatory networks at a systems level.

Personnel: Institute for Systems Biology Amardeep Kaur, Phu Van, Min Pan, Lee Pang University of Maryland – Courtney Busch, Jocelyne DiRuggiero

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Gene Regulatory networks: Combinatorial control by GTFs and TRs

Upon encountering a new environmental situation all organisms alter the expression of numerous genes to optimize their physiological state. We have discovered that the global regulatory network for this process in archaea is assembled from multiple copies of two families of general transcription factors (GTFs).  While these GTFs share lineage with eukaryotic transcription factors IIB (TFB) and TATA-binding Protein (TBP), their assembly at promoters is modulated by ~120 transcription regulators (TRs) that have common ancestry with bacterial regulators. We are using a systems approach to dissect the dynamics of how the GTFs and TRs combinatorially associate to regulate transcription of all genes in the genome.

Personnel: Institute for Systems Biology — Sacha Coesel, Tie Koide, Fang Yin Lo, David J Reiss

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Complex changes during growth

When H.salinarum NRC-1 is grown in the laboratory, we observe not only an increase in cell density but also changes in cell morphology and physiology. These adaptations are ultimately the result of complex gene regulatory networks, where a number of regulatory circuits are activated or repressed in response to complex changes in the environment. We are using a systems approach to understand the physiological adaptation that occur during growth and refining gene regulatory network models by adding mechanistic information about transcript structure and protein-DNA interaction sites.

Personnel: Institute for Systems Biology - Tie Koide, David J. Reiss, Lee Pang, Min Pan
Genome and Biomedical Sciences Facility, University of California, Davis - Marc Facciotti

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