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WP8: Computational analysis of beta-cell modular organization. EuroDia Meeting Lund, 23-25 February 2009. Sven Bergmann Department of Medical Genetics, UNIL & Swiss Institute of Bioinformatics. http://serverdgm.unil.ch/bergmann. Iterative Signature Algorithm.

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WP8:Computational analysis of beta-cell modular organization

EuroDia Meeting

Lund, 23-25 February 2009

Sven Bergmann

Department of Medical Genetics, UNIL &

Swiss Institute of Bioinformatics

http://serverdgm.unil.ch/bergmann


Iterative signature algorithm
Iterative Signature Algorithm

  • Unsupervised large-scale data analysis tool

  • Modularizes the expression matrix

  • Reduction of complexity

  • Allows for easy data integration

  • Interactive webtool


Modular analysis
Modular Analysis

  • A block of the reordered expression matrix

  • Genes and samples have scores

  • Captures differential co-expression

Transcription Module




Gábor Csárdi and Sven Bergmann

Computational Biology Group,

Department of Medical Genetics,

University of Lausanne,

Switzerland

Modular Analysis of Multi-tissue Gene Expression Data


The data set
The Data Set

  • Coming from WP2, Frans Schuit's group.

  • C57bl6 mice, plus 7 S/A islet samples

  • 23 different tissues: adrenal gland, bone marrow, brain, diaphragma, ES cells, eye, fat, fetal, gastrocnemius muscle, heart, islet, kidney, liver, lung, ovary, parotis gland, pituitary gland, placenta, seminal vesicles, small intestine, spleen, testis, thymus.

  • 3-5 samples/tissue, 89 altogether

  • 19 islet samples, 8 on high fat diet

  • After filtering based on variance: 14,540 of 45,101 probesets left on the mouse4302 array


Batch and tissue effects
Batch and Tissue Effects

Pituary gland

Islets


Spearman Rank correlation between 75 Affy mouse 430 2.0 arrays

TISSUE (n arrays)‏

High Fat Diet (5)‏

1

Islets

2

Standard Diet (4)‏

3

Pancreatic acini (3)‏

4

Adrenal (3)‏

5

Brain (3)‏

6

ES cells (3)‏

7

Adipose tissue (3)‏

8

Eye (3)‏

9

Heart (3)‏

10

Small intestine (3)‏

11

Hypothalamus (3)‏

12

Liver (3)‏

13

Lung(3)‏

14

Kidney (3)‏

15

Parotis gland (3)‏

16

Spleen (3)‏

17

Seminal vesicles (3)‏

18

Testis (3)‏

19

Thymus (3)‏

20

Diafragm (3)‏

21

Skeletal muscle (4)‏

Pituitary gland (5)‏

22

Bone marrow (4)‏

23

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23


Very preliminary modular analysis results
Very preliminary arraysModular Analysis Results

  • 977 transcription modules were identified

  • High enrichment by tissues, GO categories, KEGG pathways and transcription factors

  • Condition plots

  • Show tissue specific modules

http://www2.unil.ch/cbg/Eurodia/isa3-html/maintable.html


Pancreas specific modules islets contaminating exocrine cells
Pancreas-Specific Modules arrays(Islets + contaminating exocrine cells)‏

  • Example: #49, 35 probes, 27 Entrez genes, 43 conditions, 19 islet samples with positive scores

  • Many pancreas related genes


Pancreas specific modules
Pancreas-Specific Modules arrays

  • Genes: Gcg, Iapp, Abcc8, Scn9a, Prss2, Pnlip, Ela3, Rab37, Cuzd1, Pnliprp2, Clps, Rnase1, Asb6, Ctrb1, BC039632, B830017H08Rik, A930021C24Rik, 2210010C04Rik, 1810049H19Rik


Pancreas specific modules1
Pancreas-specific Modules arrays

  • Module #49

  • Differentiates between islets and other tissues


Islet specific go enrichment
Islet specific GO enrichment arrays

P-value # Category

5.03e-7 49 digestion

1.25e-12 10 extracellular region

3.18e-5 20 mitochondrion

1.44e-4 25 proton-transporting ATP synthase

complex, catalytic core F(1)‏

1.04e-6 64 serine-type endopeptidase activity1.49e-4 151 endopeptidase activity

3.33e-4 16 structural constituent of ribosome


Islet specific kegg enrichment
Islet specific KEGG enrichment arrays

P-value # Category

4.37e-6 16 Ribosome

3.26e-4 155 Oxidative phosphorylation


Islet specific mirnas
Islet specific miRNAs arrays

P-value # Category

6.65e-3 892 miR-30 family



High fat diet islets
High Fat Diet Islets arrays

  • Running ISA on the 19 islet samples only

  • Only 8,288 probesets after filtering

  • Module #41 differentiates between HF/LF diets best:

http://www2.unil.ch/cbg/Eurodia/isa5-html/maintable.html


High fat diet islets1
High Fat Diet Islets arrays

  • Condition scores significantly differ, p-value: 8.5*10-3

  • Significantly enriched for serine-type endopeptidase activity, p-value: 3*10-12

  • Enriched for regulation by Trypsin GTF, p-value: 3*10-14


High fat diet islets2
High Fat Diet Islets arrays

  • Module #41

  • 58 probes, 45 Entrez genes

  • Two outliers


Acknowledgements
Acknowledgements arrays

UNIL CBG:

Zoltán Kutalik

Micha Hersch

Aitana Morton

Diana Marek

Barbara Piasecka

Bastian Peter

Karen Kapur

Alain Sewer

Toby Johnson

Armand Valsessia

Gabor Csardi

Sascha Dalessi

KU Leuven:

Leentje van Lommel

Frans Schuit

Thanks to EuroDia!

http://serverdgm.unil.ch/bergmann


High fat diet islets3
High Fat Diet Islets arrays

  • Serine-type endopeptidase activity, GO molecular function category


High fat diet islets4
High Fat Diet Islets arrays

  • Intersection of module #41 and “Serine-type endopeptidase activity”, GO molecular function category


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