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A Tale of Three Inferences

A Tale of Three Inferences. Models of transcription and their consequences Philip Benfey, Ken Birnbaum, Dennis Shasha. What is the Logic of Transcription?. Known: transcription factors bind to small subsequences of DNA, perhaps in a statistical mechanical (hence concentration dependent) way.

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A Tale of Three Inferences

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  1. A Tale of Three Inferences Models of transcription and their consequences Philip Benfey, Ken Birnbaum, Dennis Shasha

  2. What is the Logic of Transcription? • Known: transcription factors bind to small subsequences of DNA, perhaps in a statistical mechanical (hence concentration dependent) way. • Controversial: interaction among different transcription factor-binding events.

  3. Models of Interaction • Additive (Boolean OR): For promoter P on gene G, if T1 binds to c1 and T2 binds to c2 in an inductive way, then the expression of G will remain the same if the promoter were to have twice the number of c1 and c2 goes to 0. • Boolean AND: Under same conditions, there will be no expression

  4. Classical Approach • Detailed nature of interaction is unknown. • Find genes whose expressions correlate well with one another. • Infer that common motifs among the promoters of those genes must be the binding cis-elements.

  5. Note to ken • Ken, please include a power point slide in which you show how this correlation method is meant to work.

  6. Bussemaker, Siggia, et. al • Model: expression of a promoter is: • S coef * number, where coef[j] is the strength of the jth transcription factor-cis-element binding and number[j] is the number of times the cis-element appears. • Additive, Boolean disjunctive model. • No explicit model of transcription factors.

  7. Bussemaker Discovery • Consider one experiment consisting of many gene-promoter pairs some of which are expressed. • Best cis-element (largest coefficient) is one that appears in promoters of many expressed genes and few unexpressed genes (inversely weighted by number of appearances per promoter)

  8. Bussemaker Example • Promoter 1: x, x, x, y. Expression: 1 • Promoter 2: x, y. Expression 1. • Promoter 3: x, y, y, y. Expression 3. • Conclude: best hypothesis is that each y contributes to expression with a coefficient of 1. No good model for x.

  9. NYU (Birn,Benf,Sha) Model • Transcription factor/cis-elements form a boolean (AND/OR/NOT) model with amplifiers (e.g. TFA & TFB ==> TFC) • Finding these circuits is a multi-stage affair: 1) find cis-element/transcription factor pairs 2) infer boolean circuit by seeing combinations that work.

  10. NYU Find TF/Cis-element pairs • Given the knowledge of genes that encode transcription factors and given a sequence of experiments (e.g. different times during sporulation), find cis-elements that correlate best with transcription factors over time.

  11. NYU Model Details • Cis-element c expression at time t = sum of expression of genes containing c in their promoter sequence. • Transcription X expression at time t = extent of RNA production at time t. • X binds to c potentially if two time sequences correlate well.

  12. Note to Ken • Ken, please put in our experiment with promoters A, B, C such that first promoter has AB, second has AC, and third has BC. First time has TA, TB; second time has TA, TC; and third time has TB, TC. • Gene correlation doesn’t work. • Bussemaker only partly works.

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