Expression2KinasesMRNA PROFILING LINKED TO MULTIPLE UPSTREAM REGULATORY LAYERS

Rafael Diego Macho Reyes (b02marer@uco.es)

Summary

1. What is the X2K software?

2. Introduction: why do we need this new tool?

1. Work proposal.

3. Work flow.

4. Reviewed cases using X2K:

1. Recovering of drug-related pathways.

2. Obteining global views of cellular differentiation.

3. Unraveling regulatory mechanisms of breast cáncer.

4. Expression data from physiological process:

1. Liver fibrosis disease gene expression.

2. Hippocampal neurons development.

5. Perspectives.

6. References.

What is the X2K software?

It is software to identify, characterize and set new upstream proteinsrelated to gene expression.

http://www.maayanlab.net/X2K/documentation.html

2. Introduction:

why do we need this new tool?

Control

Treatments

Disease

Diferent times

There is always a variation within the expression of several genes,

but most of them have unknown functions in the context of a

gene network.

By a better knowledge on gene-protein networks:

1. We could improve culture and diferentiation techniques.

2. There would be able to have a better physiological

knowledge for each person, towards further indivudal

pharmacology.

KO experiments

Over-expression

3. Work flow

3. Work flow: gene differential expression.

Cluster A Cluster B Cluster C Cluster D Cluster E

3. Work flow: upstream TF ID.

Cluster C

Most likely

Transcription

Factors

• It considers variations into thechromatine under different conditions.

• DB = >36000 interactions + > 159 relationships (gene/protein)

ChEA

• It scans promotersequences.

Transfac(PWM)

• It is another PWM algorithm

analyzer.• PWMs algorithms have better number of

references in human and mice genes and TFs.

Jaspar

(PWM)

3. Work flow: connecting proteins to TFs.

• ENTREZ human references

• InteractomeDB.

Input

• It makes therelationship betweengenes and proteinswith “signalome” and “interactome”.

X2K (G2N)• Genes-

transcriptomemost suitableproteins list. (LIST)

Output

3. Work flow: connecting proteins-TFs to kinases.

•LIST

•Kinases Databases

•> 14000 interactions.

•> 3400 publications.

•>436 kinases

Input

• It compares and infersalso the most suitablekinases.

• It uses Fisher´s Test tohave more sharpenedanalysis.

X2K (KEA)•More suitable kinases

to phosphorilateprotein complexesrelated to TFs.

Output

3. Work flow

4.Reviewed cases using X2K:

Drug receptorsNetworks

X2K

Regulatormechanisms in breast cancer

subtypes

Gene expressionvariations

through celldiferentiation

Diferentiationof

hyppocampusareas

Gene expressionvariationsthroughhepatycfibrosis

Drug receptorsNetworks500 upstream genes

500 downstream genes

Results

Analysis

Kinases

TF Complexes

Transcription factors

Gene expressionvariations

through celldiferentiation

Embryo

Differentialgene

expression

Expressionmodules

TF and PseudoTF

activiy

GATE Software

Statisticanalysis

Results

Matrixes of Expression

Pij= maxM * Akj * Eij *Iij

Input

Output

Regulatormechanisms

in breastcancer

subtypes

Diferentiationof

hyppocampusareas

Gene expressionvariationsthroughhepatycfibrosis

Upregulating Proteins

Regulating proteins

Transcription factorsTcf3

Wnt4

RSK

Regulating proteins

Already confirmed

by bibliography

CamK4

CREB

5. Perspectives

1. This is a new rational approximation to the identification and ranking of upstream

regulating proteins in differential expression genes.

2. It can be widely useful to discover new drug-receptors, and new signaling networks in

different cell types and patients, giving an enormous step on individual pharmacology.

3. In a close future it would integrate new data from histone modifications, miRNA andpost-transcriptional modifications.

4. This technique is limited by the use of too many previous work and the assumption of the

Independence between targets and regulations.

References.

Chen, Xu, Gordonov, Lim, Perkins and Ma´ayan:

“Expression2Kinases: mRNA profiling linked to multiple upstream

regulatory layers”. Bioinformatics, 28, 1 (2012), 105-111.