[Todos] Charla Gustavo Stolovitzky - Systems Biology of small and large scale gene regulatory networks

[Ariel Chernomoretz]

El día martes 30 de marzo a las 11am, el Dr. Gustavo Stolovitzky (
http://domino.watson.ibm.com/comm/research_people.nsf/pages/gustavo.index.html)
dará una charla en el aula Federman, Pabellón 1.

Quedan todos invitados.

Título: Systems Biology of small and large scale gene regulatory networks

Resumen: Technologies such as gene expression arrays and
ChIP-on-chip/ChIP-seq have emerged as powerful tools to dissect the complex
network of gene regulatory interactions between transcription factors and
their targets. I will present a newly developed algorithm with improved
sensitivity in detecting binding events from ChIP-on-chip data applied to
human T cells, followed by extensive biochemical validation. This analysis
reveals that 3 oncogenic transcription factors, NOTCH1, MYC, and HES1, bind
to several thousand target gene promoters, up to an order of magnitude
increase over conventional analysis methods. The increased sensitivity
reveals a combinatorial regulatory program in which MYC co-binds to
virtually all NOTCH1-bound promoters. This large scale complexity in the
topology of transcriptional regulatory networks, which highlights the
fundamental importance of genome-scale analysis to represent transcriptional
programs, gives however a limited level of detailed quantitative information
on the system. Therefore these approaches need to be complemented with more
detailed modeling of the biological system if we want to understand the
details of the dynamics that arise when we zoom in smaller scale behavior.
To highlight the richness of the dynamics at the smaller scales, we discuss
the concentration oscillations in the p53 signaling pathway when a cell's
DNA is damaged. In our model, the presence of double stranded DNA breaks is
transduced by ATM, a kinase that acts as the input to a downstream
oscillator consisting of a p53-Mdm2 autoregulatory feedback loop. Our
simulations results show that p53 and Mdm2 exhibit a coordinated oscillatory
dynamics upon IR stimulation, with a stochastic number of oscillations whose
mean increases with IR dosage, in good agreement with the observed response
of p53 to DNA-damage in single-cell experiments. The proposed model allows
for specific predictions. In yet another decrease in scale, we will discuss
how a single nucleotide polymorphism in the mdm2 gene (SNP309), which
enhances mdm2 transcription levels, can make p53 oscillations
disappear.  Indeed, oscillations of p53 and Mdm2 are observed in the cells
wild type for mdm2 SNP309 but not in cells homozygous for mdm2 SNP309.  In
summary, we will go from the large scale organization of the cell's gene
regulatory network, down to smaller scales and higher levels of detail, to
explore the dynamics of a cellular pathway that, threading at finer scales
can be disrupted by a single nucleotide polymorphism.



-- 
Dr. Ariel Chernomoretz
      Departamento de Fisica, FCEyN,        Universidad de Buenos Aires,
      (1428) Ciudad Universitaria,        Ciudad de Buenos Aires, Argentina.
      TE +54 11 4576 3390 ext 817
      Fax +54 11 4576 3357
      email: ariel en df.uba.ar        Webpage:
http://www.df.uba.ar/users/ariel
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