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

[Lista de los Alumnos del Departamento de Fisica]

Aunque no confirmamos, debería ser en castellano.

---------- Forwarded message ----------
Date: Mon, 29 Mar 2010 09:49:22 -0300
From: Ariel Chernomoretz <ariel en df.uba.ar>
To: todos en df.uba.ar, todos en fbmc.fcen.uba.ar, todos en qb.fcen.uba.ar,
     alumnos en df.uba.ar
Subject: [Todos] Charla Gustavo Stolovitzky - Systems Biology of small and large
      scale gene regulatory networks

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