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Transcript
Mapping the DNA Damage Response Case study reveals transcription factor (TF) modules, dynamic TF binding and an expanded role for cell cycle regulators Overview • Experimental factors and selection – Multiple criteria used • ChIP-on-chip – Differential binding analysis • Gene expression of TF-deletion mutants – Clustering analysis – Deletion-buffering analysis • Data integration and pathway reconstruction Overview of the approach Overview of the approach Overview of the approach Transcription factors that regulate DNA damage response Activated regulatory network Transcription factors that regulate DNA damage response Activated regulatory network TF knockout “Deletion-buffered” Growth phenotype in MMS: mutants that display relative growth inhibition Truncated Product Method (TPM): determine condition dependent binding ChIP-chip of 30 TFs before and after DNA damage YPD MMS +/-MMS TPM ChIP-chip Data Summary TFs may regulate different genes (bind different promoters) under different conditions. Workman CT, Mak HC, McCuine S, Tagne JB, Agarwal M, Ozier O, Begley TJ, Samson LD, Ideker T. A systems approach to mapping DNA damage response pathways. Science. 2006 May 19;312(5776):1054-9. Promoter regions analysis ChIP-chip and DNA-Motif TF-Knockout expression profiles: (look much like wild-type) Environmental “epistasis analysis”: (deletion-buffering) Deletion-buffering analysis Bayesian Score Deletion-buffering examples RNR Genes are repressed by Rfx1p Sensitive TFs are required for a greater number of damage responsive genes Integrated model (regulatory paths explaining buffered genes) Pathway reconstruction Pathway reconstruction Pathway reconstruction Integrated direct and indirect regulatory pathways (chIP-chip, prot-prot) that explain deletionbuffering relationships Workman CT, Mak HC, McCuine S, Tagne JB, Agarwal M, Ozier O, Begley TJ, Samson LD, Ideker T. A systems approach to mapping DNA damage response pathways. Science. 2006 May 19;312(5776):1054-9. Summary • “Sensitive” TFs control more of the DNA damage response than non-sensitive TFs • Regulatory networks are highly interconnected • Transcriptional regulation of important DNA damage checkpoint kinases are observed • Measuring differential TF-binding is difficult
