Physics and Thermodynamics Help Assess DNA Defects in Cancer

Physics and Thermodynamics Help Assess DNA Defects in Cancer

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  • ‘Big data’ cancer research has revealed a new spectrum of genetic mutations across tumors that need understanding.
  • Existing methods for analyzing DNA defects in cancer are blind to how those mutations actually behave.
  • ISB scientists developed a new approach using physics- and structure-based modeling to systematically assess the spectrum of mutations that arise in several gene regulatory proteins in cancer.

A significant challenge in cancer research is having the right tools and methods to analyze the myriad data generated by large-scale projects such as The Cancer Genome Atlas. Existing methods are too statistical and are blind to the way in which mutations actually affect protein function and biophysical mechanisms.
Researchers at Institute for Systems Biology have developed a new method that systematically investigates how small mutations in the DNA sequences that encode proteins result in structural and energetic changes that impact protein function. This study, a collaboration of the Baliga and Shmulevich labs, simulated the physics and energetics of protein structure and function in order to assess the impacts of a broad spectrum of protein mutations that have been observed in human cancers. Specifically, researchers considered mutations in proteins called transcription factors that regulate cellular function in order to predict and identify the putative effects of these mutations on gene expression and cell regulatory pathways.

Title: Structure-based predictions broadly link transcription factor mutations to gene expression changes in cancers
Journal: Nucleic Acids Research
Authors: Justin Ashworth, Brady Bernard, Sheila Reynolds, Christopher L. Plaisier, Ilya Shmulevich, Nitin S. Baliga
Link: http://nar.oxfordjournals.org/content/early/2014/11/05/nar.gku1031.full
Critical losses of protein function in gene regulatory proteins and tumor suppressors can lead to cellular dysregulation and the hallmarks of cancer. Using a physics-based approach to assess the impacts of mutations resulted in higher mechanistic accuracy in determining links between mutations in transcription factors and changes in gene expression. The method also illustrates a quantitative relationship between the relevant thermodynamic impacts of each unique protein mutation and its prevalence in cancerous tissues.
Integrating molecular biophysics and structure-based modeling into systems-based analyses of disease mutations will improve understanding of the molecular genetics of cancers and to interpret the complex data about mutations that are now available.
Read more about ISB’s work with The Cancer Genome Atlas project.

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Diatom Portal

Diatom Portal

http://networks.systemsbiology.net/diatom-portal

The Diatom Portal is a new resource for the diatom community. It's aim is not only to provide a repository for experimental and computational results, but to be used as an interface to existing resources. Our hope is to continue expanding this resource for many diatoms including T. pseudonana.

References

in preperation

How One Family of Microbial Genes Rewires Itself for New Niches

How One Family of Microbial Genes Rewires Itself for New Niches

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  • When an organism duplicates its genes, it increases its ability to adapt and colonize new environments.
  • ISB researchers used the systems approach to study how one family of microbial genes evolved to bring functions that were adaptive to specific environments.
  • This new understanding of how gene regulatory networks rewire themselves has many potential applications, including how to wire new functions into an organism for biofuel production, bio-remediation or bio-pharmaceutical production.

In a study to better understand how regulatory proteins function in controlling physiological processes, ISB researchers have discovered how one family of microbial genes evolves to increase its ability to adapt to specific environments. This insight about how the gene regulatory network rewires itself has the potential to inform the rewiring of organisms used for biofuel production, bio-remediation or bio-pharmaceutials.
The study, published on Nov.14 in BMC Systems Biology, used a systems perspective to look into the evolutionary processes that allow duplicated transcription factors (TFs), or DNA binding proteins, to adapt to new environmental challenges. TFs push the expression sets of genes up or down based on environmental conditions and interactions. By using the systems approach, ISB researchers were able to assign function and context to TFs not previously understood.
In order to adapt to new environments, organisms can move functions to new contexts by duplicating the regulatory factors that control that process and then allowing the copies to diverge through variation in promoter sequences, DNA binding domains, or effector molecule sensing domains. Researchers studied eight gene duplications of the Feast/Famine/ Regulatory Protein (FFRP) family in Halobacterium salinarum. By studying this TF family, – specifically its DNA binding locations, metabolite affinities and influence on gene expression patterns for 35 different environmental and nutritional conditions – researchers were able to demonstrate variable regulation arising from similar genetic ancestry. Organisms fine-tune their regulatory networks by evolutionarily tweaking the context in which similar regulatory proteins function or operate.
Researchers also developed a new way to integrate protein analysis technologies to discover how specific TFs behave given a specific context. (ISB also has applied this approach to researching the genetic adaptability of M. tuberculosis.) The study shows that these context-dependent regulatory effects have real biological consequences on the fitness of the organism.
This novel approach of integrating evolutionary context with gene regulatory networks greatly increases the possibilities for how organisms can be rewired for industrial applications related to biofuels, bio-remediation and bio-pharmaceuticals.

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