Lecture 3: Statistical Mechanics of Gene Regulation Rob Phillips California Institute of Technology (Schulten et al.) (Small et al.)

How Big is a Genome?

“The Great Polymer Languages”

A Reminder on DNA: One of the “Great Polymer Languages”

The Meaning of a Terabyte 1 gggcggcgac ctcgcgggtt ttcgctattt atgaaaattt tccggtttaa ggcgtttccg 61 ttcttcttcg tcataactta atgtttttat ttaaaatacc ctctgaaaag aaaggaaacg 121 acaggtgctg aaagcgaggc tttttggcct ctgtcgtttc ctttctctgt ttttgtccgt 181 ggaatgaaca atggaagtca acaaaaagca gctggctgac attttcggtg cgagtatccg 241 taccattcag aactggcagg aacagggaat gcccgttctg cgaggcggtg gcaagggtaa 301 tgaggtgctt tatgactctg ccgccgtcat aaaatggtat gccgaaaggg atgctgaaat 361 tgagaacgaa aagctgcgcc gggaggttga agaactgcgg caggccagcg aggcagatct 421 ccagccagga actattgagt acgaacgcca tcgacttacg cgtgcgcagg ccgacgcaca 481 ggaactgaag aatgccagag actccgctga agtggtggaa accgcattct gtactttcgt 541 gctgtcgcgg atcgcaggtg aaattgccag tattctcgac gggctccccc tgtcggtgca 601 gcggcgtttt ccggaactgg aaaaccgaca tgttgatttc ctgaaacggg atatcatcaa ………………… catgaggttg ccccgtattc agtgtcgctg atttgtattg tctgaagttg tttttacgtt aagttgatgc agatcaatta atacgatacc tgcgtcataa ttgattattt gacgtggttt gatggcctcc acgcacgttg tgatatgtag atgataatca ttatcacttt acgggtcctt tccggtgatc cgacaggtta cg (Thanks to Farid Abraham)

Sizing up E. Coli

A Reminder on the Central Dogma

Lifestyles of Bacteriophage

Gene Regulatory Decisions: The Case of Phage Lambda Phage lambda can either lay in wait or immediately reproduce. Viral life cycle dictated by regulatory decisions – the lambda switch.

Gene Regulation and Development: Case of Drosophila (Berman et al.) Spatial patterns of gene expression lead to anterior- posterior polarity. Gradients in regulatory proteins.

The Great Idea of Jacob and Monod: Genes that Control Genes Observations on phage life cycle and bacterial growth in presence of different sugars led to picture of gene regulation. Use of sugars other than glucose (such as lactose) seemed to be tightly controlled. (Muller-Hill)

How Are Genes Regulated? Genes can be regulated at many stages along the path from DNA to protein. Transcriptional control is one of the most important mechanisms and will be the focus of our discussion.

RNA Polymerase: Bound or Not? (Cramer ‘02) (Ptashne and Gann) For us, the whole question of transcriptional regulation will come down to the question of whether or not RNAP is bound to the promoter or not! There are an array of molecules (transcription factors) that participate in recruiting RNAP to its promoter.

Repressors: The Cartoon Repressor molecules inhibit action of RNA polymerase. Repressors can be under the control of other molecules (i.e. inducers) that dictate when repressor is bound and not.

Activators: The Cartoon Activator molecules enhance the action of RNA polymerase. Activators can be under the control of other molecules (i.e. inducers) that dictate when activator is bound and not. Activators “RECRUIT” the polymerase. Adhesive interaction between RNAP and activator

All Together Now: The Lac Operon Our goal: mathematize the story told by all of these cartoons. In particular, compute the probability of RNAP binding as a function of concentration of all the other molecular actors.

Structures of the Molecular Actors in the Lac Drama (Beautiful work of David Goodsell) RNAP+DNA+mRNA Lac Repressor CRP and DNA Products of the Lac Operon

Repression level depends upon the spacing of the operators. Once again, we assert that the dynamical definition can be replaced by an equilibrium description. Repression in the Lac Operon: the Role of Looping