Gene Regulatory Networks and Neurodegenerative Diseases Anne Chiaramello, Ph.D Associate Professor George Washington University Medical Center Department of Anatomy and Cell Biology Tel: 202-994-2173 [email protected]NIH/NINDS R01NS041391 McCormick Pilot Grant January 24, 2007
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Gene Regulatory Networks and Neurodegenerative Diseases Anne Chiaramello, Ph.D Associate Professor George Washington University Medical Center Department.
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1-Microarray analysis does not directly reveal the regulatory networks that underliethe observed transcriptional module mediated by NeuroD6. Combining promoter analysis with microarray results can shed light on NeuroD6-regulated networks2-A promoter is defined as a functional region immediately upstream and downstream of a Transcriptional start site (TSS) that is ultimately involved in the regulation of transcription.
3-The putative TSS for 17,702 transcripts corresponding to 13,300 genes have been annotated. Given a correct estimate of ~25,000 human genes, promoters for a majority of genes in the human genome remain to be fully defined.4-Furthermore, transcriptional regulation of most genes originates from at least two distinct promoters,located in different non-coding exons, with the upstream promoter most of the time unknown.
Computational Approaches to Identify the Underlying Transcriptional Network
of Gene Expression from Microarray Analysis.
Core Promoter (-250/+150 bp)
Enhancers Proximal Promoter (5’UTR)TSS
DPEInr+1
TATA
-2000 bp +28-32 bp-35-25 bp
Ab Initio Methods to Predict Promoter Structure
•Database of Transcription Start site (db TSS)
•Cold Spring Harbor Laboratories Mammalian promoter
Database
•Genome Browser: UCSC, ENSEMBL, NCBI
•Cap Analysis of Gene Expression (Riken, CAGE Data)
•Promoter Predictions Algorithms
•GRAIL Exp v3.3 (Gene Recognition and Analysis Internet
work)•Promo H Algorithm•Promoter Inspector•Dragon Promoter Finder•De novo FIRST EF ( First Exon-Finding)
Prediction of Transcription Factor Binding Sites (TFBS)
•To reduce false positives, focus on:• binding sites conserved among conserved species identified by several algorithms.•Position Weight Matrix comparison•Module Searcher