Tuesday, June 2, 2015

Gene expression by the numbers, day 0: Big picture questions about transcription

(Day 0Day 1Day 2Day 3 (take Rorschach test at end of Day 3!))

So just about to get on a plane to go to Boston/Cambridge for a meeting on transcription–I think it's going to be a lot of fun! Bunch of folks with a quantitative bent getting together, including the organizers Al Sanchez, Hernan Garcia, Jané Kondev, Angela DePace and Rob Phillips (big thanks for all their hard work!). The big reason I'm excited is that this is not going to be a typical meeting: the goal is to discard with the usual formalities of a meeting (like a bunch of boring talks that nobody pays attention to) and instead actually talk with each other about where we want the field to head and how we might get there. We even all made short videos beforehand as a sort of pre-conference introduction!

This is going to require changing our usual scientific behavior, which is to stamp out wild ideas as soon as we hear them. You know that crazy person who asks you some weird question at the end of your seminar about bees and the number 12? Well, that's going to be me, and I won't be satisfied with "talking about it later off-line". :)

Nor is it going to be completely off-line. I'm going to blog about the goings-on in the hope that others can participate as well in what is sadly (but perhaps necessarily) a rather small event. So drop me a line if you have any burning questions about transcription.

What are the sorts of questions we'll be discussing? Here's a few I’ve been thinking about after watching everyone’s videos:
  1. How close are we to a predictive understanding of the regulatory code? I.e., if I give you a cell type and a piece of DNA, can I predict how much transcription there will be?
  2. (Related bonus question) How do we deal with the complexity of metazoan transcriptional regulation? What new conceptual frameworks will we need to make further progress?
  3. What are some new methods that we could develop that would help us understand transcription? What are the quantities that we would like to measure?
  4. Development appears to be incredibly precise–how do developing organisms achieve this despite the sloppiness of chemical reactions? To what extent is this precision an intrinsic property of the cell and to what extent is it an emergent property of the interaction of different cells?
  5. What are the functional consequences of transcription? Which aspects of transcription “matter” and which ones are irrelevant? In chemistry, we talk about rate-limiting reactions. What are the biology-limiting reactions in transcription? What should we be measuring?
More soon!


  1. Is there a website for info/talk videos?

  2. Arjun, I am looking forward to reading about what seems to be a very promising discussion. Some interesting questions that come to mind are:

    TFs can activate some genes but repress other genes: Are these opposite regulatory functions achieved by distinct TF domains or by the same domain in different context/interaction environments ?

    More generally, can the interactions between TFs regulating the same gene be decomposed into single TF terms or do they contain irreducible many-body-interaction terms ?

  3. related to #1: can we determine the relative contribution of each regulatory element (cis & trans) to the transcription of a particular RNA?

    Is there anything else in the cell that is directly regulating transcription, besides DNA elements, RNAs & proteins?

    (ooch! had a long reply which disappeared before posting. let's try again:)

    Related to #5: "abortive transcription", "transcriptional noise" and other names to what may or may not be non-productive transcription: A) are we able to accurately differentiate it from productive transcription? B) What is it's (quantitative) contribution to transcription regulation? C) What is it's contribution to cell function/viabiliy?

    Here's a fun one: How did transcription appear during evolution? Can we determine the most basic, simple, bare minimum requirements to make RNA on a DNA template in the assumed proto-cell environment? Will understanding this help us understand modern transcription better? Will it help us in molecular bio or synthetic bio research?

    1. (that "ooch" line was supposed to be the first line. what is going on??? can't even properly complain...)

    2. Gal, these are great, thanks!

  4. I'm sure Angela will raise this issue: Right now equilibrium thermodynamic models are among the most effective and widely used ways decipher regulatory codes and predict gene expression from sequence. How do we extend/reconcile these models with non-equilibrium and stochastic aspects of transcription?

    1. Hi Mike, this is an excellent question, and one that we discussed a bit during the meeting. I'm not sure that we came up with anything spectacular at the meeting. We actually didn't really talk about stochastic aspects very much at all, and I really wonder what the connection is between transcriptional bursts and these mechanistically-inspired models.