BiblioSphere - Genomatix
BiblioSphere - Genomatix
BiblioSphere - Genomatix
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<strong>Genomatix</strong><br />
ElDorado<br />
<strong>BiblioSphere</strong> GEMS Launcher<br />
• Knowledge driven<br />
data analysis<br />
<strong>Genomatix</strong>Suite<br />
• Functional genome<br />
annotation<br />
Company<br />
• Functional analysis of<br />
promoter sequences<br />
© 2004 by <strong>Genomatix</strong> Software GmbH
<strong>Genomatix</strong> WebEx <strong>Genomatix</strong><br />
The breast cancer example<br />
BRCA1 and BRCA2 are associated with hereditary breast cancer<br />
D-cyclins are also associated with breast cancer<br />
?<br />
BRCA1,2 D-Cyclins<br />
Breast Cancer<br />
Is there a functional connection between BRCAs and D-cyclins?<br />
© 2004 by <strong>Genomatix</strong> Software GmbH
<strong>Genomatix</strong> Literature & sequence analysis<br />
Strategy for analysis<br />
Analyze literature for connections BRCAs - D-cyclins (<strong>BiblioSphere</strong>)<br />
Determine nature of connection (<strong>BiblioSphere</strong>)<br />
Analyze connection on molecular level (GEMS & <strong>BiblioSphere</strong>)<br />
Promoter analysis of connected genes (ElDorado & GEMS & <strong>BiblioSphere</strong>)<br />
Combine evidence from literature and sequence analysis<br />
Summary<br />
Is there a functional connection between BRCAs and D-cyclins?<br />
© 2004 by <strong>Genomatix</strong> Software GmbH
<strong>Genomatix</strong> Literature analysis<br />
Co-citation environment ob BRCA1 and BRCA2<br />
BRCA1 and BRCA2 were search terms in <strong>BiblioSphere</strong><br />
200 genes were cocited with both BRCA1 and BRCA2 at least twice<br />
© 2004 by <strong>Genomatix</strong> Software GmbH
<strong>Genomatix</strong> Literature analysis<br />
Categorization of results for biological functionality<br />
<strong>BiblioSphere</strong> quantitates association with filter criteria<br />
Categorization by z-score rating<br />
27 genes in category “cell cycle”<br />
Those 27 genes reach z-score 18.7<br />
D-Cyclin CCND1 is within this group<br />
Size of gene group reduced 7.4-fold!<br />
Co-citation filter: sentence level; genes are 2 times co cited. Filter category: GO “biological process“<br />
© 2004 by <strong>Genomatix</strong> Software GmbH
<strong>Genomatix</strong> Literature analysis<br />
BRCA, BRCA2, and CCND1 are associated with cell cycle<br />
<strong>BiblioSphere</strong> determined this association as most significant<br />
CCND1 is tightly associated with CCND2 and CCND3<br />
Therefore CCND2 and CCND3 were included in the analysis<br />
New cluster-centered <strong>BiblioSphere</strong> generated with:<br />
BRCA1<br />
BRCA2<br />
CNND1<br />
CCND2<br />
CCND3<br />
Selection of new seed genes was based on results of previous analysis<br />
© 2004 by <strong>Genomatix</strong> Software GmbH
<strong>Genomatix</strong><br />
Literature analysis<br />
Bibliosphere of BRCA1, BRCA2, CCND1, CCND2, CCND3<br />
BRCA1<br />
BRCA2<br />
CCND1<br />
CCND2<br />
CCND3<br />
No direct link between BRCAs<br />
and CCND2 and CCND3<br />
BRCA1<br />
BRCA2<br />
CCND1<br />
CREB1<br />
CCND2<br />
CCND3<br />
BRCAs are linked to CCND2<br />
and CCND3 via CREB1<br />
© 2004 by <strong>Genomatix</strong> Software GmbH
<strong>Genomatix</strong> Literature analysis<br />
<strong>BiblioSphere</strong> direct links to PubMed<br />
Cocitation BRCA1-CREB<br />
CREB acts as a consecutive<br />
positive element of BRCA1<br />
Cocitation CCND3-CREB<br />
CCND3 has an upstream<br />
CREB binding site<br />
Annotated PubMed abstracts allow one-click verification of cocitation link<br />
© 2004 by <strong>Genomatix</strong> Software GmbH
<strong>Genomatix</strong> Literature & sequence analysis<br />
<strong>BiblioSphere</strong> transcription factor binding site analysis (TFBS)<br />
Link of BRCAs and D-Cyclins via CREB1 is confirmed by TF-analysis<br />
© 2004 by <strong>Genomatix</strong> Software GmbH
<strong>Genomatix</strong> Sequence analysis<br />
Promoter analysis by GEMS based on ElDorado data<br />
Literature Analysis<br />
<strong>BiblioSphere</strong><br />
Promoter analysis<br />
ElDorado<br />
GEMS<br />
Results from literature analysis are used to guide sequence analysis<br />
© 2004 by <strong>Genomatix</strong> Software GmbH
<strong>Genomatix</strong> Sequence analysis<br />
Promoter analysis of BRCA1, BRCA2, CCND1, CCND2, CCND3<br />
ElDorado<br />
GEMS<br />
Gene Annotation<br />
Comparative Genomics (CompGen promoters)<br />
Extraction of orthologous promoter-sequences<br />
Construction of models: FrameWorker<br />
Evaluation of models: ModelInspector<br />
Each gene is subject to comparative analysis of orthologous promoters<br />
© 2004 by <strong>Genomatix</strong> Software GmbH
<strong>Genomatix</strong> Sequence analysis<br />
ElDorado comparative genomics of promoters<br />
Promoters of BRCAs and D-Cyclins<br />
21 Sequences for human mouse and rat (including alternative promoters)<br />
Example: CCND2<br />
© 2004 by <strong>Genomatix</strong> Software GmbH
<strong>Genomatix</strong> Sequence analysis<br />
FrameWorker analysis for common elements in all promoters<br />
CREB is the only common binding site (1190 TFBSs serached)<br />
© 2004 by <strong>Genomatix</strong> Software GmbH
<strong>Genomatix</strong> Sequence analysis<br />
Intergenomic versus intra-genomic frameworks<br />
genes<br />
human<br />
mouse<br />
rat<br />
BRCA1 BRCA2 CCND1 CCND2 CCND3<br />
Comparative analysis of promoters within one species -> coregulation<br />
Comparative genomics of promoters -> phylogenetic conservation<br />
© 2004 by <strong>Genomatix</strong> Software GmbH
<strong>Genomatix</strong> Sequence analysis<br />
FrameWorker analysis of orthologous promoters (inter-genomic)<br />
Framework found in human, mouse, and rat BRCA1 promoter<br />
ETS-CREB-ECAT model confirmed:<br />
McCoy et al. Reproductive Biology<br />
and Endocrinology (2003) 1:72<br />
ETS CREB ECAT<br />
- - +<br />
CREB is part of a functional framework in BRCA1 promoters<br />
© 2004 by <strong>Genomatix</strong> Software GmbH
<strong>Genomatix</strong><br />
Sequence analysis<br />
All FrameWorker results from comparative genomics analysis<br />
CREB1<br />
BRCA1: CREB<br />
BRCA2:<br />
P1:<br />
P2:<br />
CCND1: P1:<br />
CCND2:<br />
P1:<br />
CCND3: Promoter 1-3: only binding sites (no frameworks)<br />
All promoter groups except CCND3 contain CREB1 in an inter-genomic framework<br />
CREB<br />
CREB<br />
CREB<br />
CREB<br />
CREB<br />
© 2004 by <strong>Genomatix</strong> Software GmbH
<strong>Genomatix</strong> Sequence analysis<br />
FrameWorker intra-genomic analysis of human promoters<br />
BRCA1, BRCA2, and CCND2 share a specific framework<br />
CREB<br />
Only 10 additonal matches in all human promoters (50,000)<br />
4 of these additional matches are asssociated with breast or cancer<br />
BRCA genes and cyclin D2 are most likely transcriptionally coregulated<br />
© 2004 by <strong>Genomatix</strong> Software GmbH
<strong>Genomatix</strong><br />
Combination of evidence<br />
Joining <strong>BiblioSphere</strong> and FrameWorker results<br />
BRCA1<br />
CREB1<br />
Inter-genomic<br />
framework<br />
BRCA2<br />
CCND1<br />
CREB1<br />
CCND2<br />
CREB1<br />
human<br />
framework<br />
Conservation of CREB in frameworks emphasizes biological functionality<br />
CCND3<br />
© 2004 by <strong>Genomatix</strong> Software GmbH
<strong>Genomatix</strong><br />
Generating new knowledge<br />
New knowledge<br />
BRCAs<br />
Prior knowledge<br />
Creating concepts<br />
CREB1<br />
human<br />
framework<br />
Concept<br />
?<br />
Breast Cancer<br />
D-Cyclins<br />
Strong evidences that CREB signaling is involved in breast cancer development<br />
© 2004 by <strong>Genomatix</strong> Software GmbH
<strong>Genomatix</strong><br />
ElDorado<br />
<strong>BiblioSphere</strong> GEMS Launcher<br />
Analysis strategies for:<br />
Single genes<br />
Gene clusters<br />
<strong>Genomatix</strong>Suite<br />
Results from expression arrays<br />
Much more<br />
© 2004 by <strong>Genomatix</strong> Software GmbH
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