Department of Cell and Developmental Biology
Director: Professor Dr. Hans R. Schöler

Marcos J. Araúzo-Bravo is a scientist and project leader at the MPI. As it emerges from his published work, his main research has been devoted to the development and application of computer tools for analyzing and solving biological problems. He received his doctoral degrees in industrial technologies from the University of Cartagena, Spain (2001), and in information technology and biotechnology from the Kyushu Institute of Technology, Fukuoka, Japan (2003). As a postdoctoral fellow he was granted by the Japan Society for the Promotion of Science (JSPS) to study the synergetic control of genetic networks through transcriptional regulators at the Kyushu Institute of Technology (2004-2006).

Research subjects

Development of computer tools for understanding the mechanism underlying genetic regulatory networks of the toti-, pluripotential stem cells and reprogrammed cells. To elucidate the cross talk of the main pluripotency players at the molecular level and to provide answers to the remaining questions concerning the reprogramming mechanisms, we are implementing an integrative approach collecting measurements of different nature (gene expression, microRNA expression, epigenetic profiles, protein abundance, metabolic measurements) performed in a holistic way thanks to the use of high throughput techniques, combining the measurements obtaining in our lab with data compiled from databases and gluing all these data by recycling computational biological tools and developing our own new ones.

Characterization of the properties of the genetic regulatory networks of the toti-, pluripotential stem cells

Embryonic stem cells (ESCs) have the capability for self-renewal and the potential to form all the cell types of the body. This brings the possibility to exploit ESC populations as a cellular source for therapies in medical situations with irreversible tissue damage. To make this potential a reality, we need a better understanding of the interplay of the transcription factors (TFs) and their binding sites involved in the regulation of the transcription network that determine the ability of ESCs to maintain their self-renewal and pluripotency.

In the last years, a trio of transcription factors (OCT4, SOX2, and NANOG) has been identified that plays a key role in determining the fate of ES cells. Strong efforts have been done on discovering these main players, generating large quantities of data with high throughput techniques. But the transcription regulatory network that rules the self-renewal and pluripotency states remains to be elusive.

Computational programming of biological reprogramming

A cocktail of transcription factors (OCT4, SOX2, C-MYC and KLF4) has been successfully applied to rewind the clock of unipotent cells, reverting them to a state resembling the ESC, thus acquiring self-renewal and pluripotential capabilities. Generating the so-called reprogrammed induced pluripotent (iPS) stem cells. iPS help to overcome some of the ethical concerns due to the use of human ESCs. But reprogramming does not normally occur in vivo and its mechanism is intriguing.

The four ingredients of the reprogramming cocktail have been reduced by researchers from our lab to two (Kim et al, 2008), one (Kim et al, 2009; Kim et al, 2009), and even zero (Ko et al, 2008), for some specific cell types. We expect to take advantage of this progressive complexity reduction to disentangle the reprogramming mechanisms.

Extra-mural collaborations

• Prof. Shimizu Kazuyuki, Kyushu Institute of Technology, Fukuoka, JAPAN
  
• Prof. Akinori Sarai, Kyushu Institute of Technology, Fukuoka, JAPAN
  
• Dr. Ileana Zucchi, CNR-ITB, ITALY
  

Master and doctoral positions available

Currently we are recruiting doctoral students and postdocs in computational biology and bioinformatics at the department of Cell and Developmental Biology at the Max Planck Institute for Molecular Biomedicine in Münster (Germany).

If you are interested in doing your PhD in Systems Biology and Bioinformatics or to do a postdoc in computer science applied to biology in an exciting environment at the Max Planck Institute in Münster (Germany), please contact me at marara@mpi-muenster.mpg.de

Some representative publications

Kim JB, Greber B, Araúzo-Bravo MJ, Meyer J, Park KI, Zaehres H and Schöler HR (2009).
Direct reprogramming of human neural stem cells by OCT4.
Nature. 461(7264):649-653.

Kim JB, Zaehres H, Araúzo-Bravo MJ and Schöler HR (2009).
Generation of induced pluripotent stem cells from neural stem cells.
Nature Protocols. 4(10):1464-1470.

Ko K, Tapia N, Wu G, Kim JB, Araúzo-Bravo MJ, Sasse, P, Glaser T, Ruau D, Han DW, Greber B, Hausdörfer K, Sebastiano V, Stehling M, Fleischmann BK, Brüstle O, Zenke M and Schöler HR (2009).
Induction of Pluripotency in Adult Unipotent Germline Stem Cells.
Cell Stem Cell. 5:87-96.

Kim JB, Sebastiano V, Wu G, Araúzo-Bravo MJ, Sasse P, Gentile L, Ko K, Ruau D, Ehrich M, van den Boom D, Meyer J, Hübner K, Bernemann C, Ortmeier C, Zenke M, Fleischmann BK, Zaehres H and Schöler HR (2009).
Oct4-Induced Pluripotency in Adult Neural Stem Cells.
Cell. 136:411-419.

Kim JB, Zaehres H, Wu G, Gentile L, Ko K, Sebastiano V, Araúzo-Bravo MJ, Ruau D, Han DW, Zenke M and Schöler HR (2008).
Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors.
Nature. 454(7204):646-650.

Struckmann S, Araúzo-Bravo MJ, Schöler HR, Reinbold RA and Fuellen G (2008).
ReXSpecies - A tool for the analysis of the evolution of gene regulation across species.
BMC Evolutionary Biology. 8(111):1-18.

Araúzo-Bravo MJ and Sarai A. (2008).
Indirect Readout in Drug-DNA Recognition: Role of DNA Conformational Change in the Specificity of Drug Binding.
Nucleic Acids Research. 36(2):376-386, 2008.

del Sol A, Araúzo-Bravo MJ, Amoros D and Nussinov R (2007).
Modular architecture of protein structures and allosteric communications: Potential implications to signaling proteins and regulatory linkages.
Genome Biology. 8(5):R92.

Ahmad S, Kono H, Araúzo-Bravo MJ and Sarai A (2006).
ReadOut: structure-based calculation of direct and indirect readout energies and specificities for protein-DNA recognition.
Nucleic Acids Research. 34, Web Server issue W1-W4.

Araúzo-Bravo MJ, Fujii S, Kono H, Ahmad S, Sarai A (2005).
Sequence-Dependent Conformational Energy of DNA Derived from Molecular Dynamics Simulations: Toward Understanding the Indirect Readout Mechanism in Protein-DNA Recognition.
Journal of the American Society of Chemistry. 127(46):16074-16089.

Peng L, Araúzo-Bravo MJ, Shimizu K (2004).
Metabolic flux analysis for a ppc mutant Escherichia coli based on ¹³C-labelling experiments together with enzyme activity assays and intracellular metabolite measurements.
FEMS Microbiology Letters. 235:17-23.

Zaid KS, Araúzo-Bravo MJ, Shimizu K (2004).
Effect of a pyruvate kinase (pykF-gene) knockout mutation on the control of gene expression and metabolic fluxes in Escherichia coli.
FEMS Microbiology Letters. 235:25-33.

Zaid KS, Araúzo-Bravo MJ, Shimizu K (2004).
Metabolic flux analysis of pykF gene knockout Escherichia coli based on ¹³C-labeled experiment together with measurements of enzyme activities and intracellular metabolite concentrations.
Applied Microbiology and Biotechnology. 63:407-417.

Araúzo-Bravo MJ, Cano-Izquierdo JM, Gómez-Sánchez E, López-Nieto MJ, Dimitriadis YA, López-Coronado J (2004).
Automatization of a penicillin production process with soft sensors and an adaptive controller based on neuro fuzzy systems.
Control Engineering Practice. 12:1073-1090.

Araúzo-Bravo MJ, Shimizu K (2003).
An improved method for statistical analysis of metabolic flux analysis using isotopomer mapping matrices with analytical expressions.
Journal of Biotechnology. 105:117-133.

For a complete list of publications please see.

Some microarrays uploaded in the Gene Expression Omnibus (GEO) database

• GSE16178, GSE11274: Zero-factor reprogrammed mouse germ-line-derived pluripotent stem cells (gPS).
• GSE15355: One-factor (OCT4/POU5F1) reprogrammed human neural stem cells (NSC).
• GSE12499: One-factor (Oct4/Puo5f1) reprogrammed mouse neural stem cells (NSC).
• GSE10806: Two-factors (Oct4/Puo5f1 and Klf4) reprogrammed mouse neural stem cells (NSC).

Zero-factor reprogramming. Heat-map of expression of pluripotent and germ cell marker genes extracted from gene expression microarrays, showing differential expression patterns between mouse Germ Stem Cells (GSCs), and ESCs and germ-line-derived pluripotent stem cells (gPS). (see).

One-factor reprogramming. Tri-dimensional scatter plot of the 1 factor (OCT4) reprogrammed human neural stem cells (1F hNiPS) versus H9 and H1 human embryonic stem cells (ESC). (see).

Two-factors reprogramming. Scatter plot of the 2 factor (Oct4, Klf4) reprogrammed mouse neural stem cells (2F iPS) versus embryonic stem cells (ESC). (see).

DNA recognition by drugs. Worm graph of the DNA imidazole-pyrrole-hydroxypyrrole polyamide binding complex. (see).

Metabolic engineering based on labeling techniques. Metabolic Flux Analysis of Escherichia coli pykF mutant. (see).

Allosteric communication in proteins. Modular decomposition and interconnectivity determinants identify key residues for allosteric communications in rhodopsin. (see).