Biophysics of Transcriptional Regulation

April 24, 2008

I saw a seminar this week by Leonid Mirny, a MIT physicist with a joint appointment in the Harvard–MIT Division of Health Sciences and Technology. It was an interesting talk on how biophysical models concerning how regulatory proteins search for their sites on DNA has interesting implications for genome structure.

Mirny opened by discussing the following paradox … the diffusion rates for a single protein finding a single DNA site within a 3D nucleus is roughly 3X slower than the experimentally measured value. So how does a protein find it’s DNA recognition site faster than diffusion without the consumption of energy?

The classical answer to this problem is the idea of facilitated diffusion … ie. that DNA binding proteins can bind non-specifically and reduce the 3D diffusion problem to a 1D problem by “sliding” along DNA searching. Proteins must therefore balance time spent in 1D (facilitated diffusion) versus 3D (diffusion) search modes. Mirny shows how measured values for the affinity of a protein to non-specific DNA indicates that the system is far from optimal, spending too much time on the DNA (in 1D mode). Consequently, estimated search times far are too long for most bacterial systems and facilitated diffusion is insufficient!

There are two ways to overcome the problem. The first is a concentration effect … make so much transcription factor that each molecule is responsible for only a small portion of the search space. The second is to utilize co-localization … imposing constraints on the search space which favor the transcription factor finding it’s DNA site. Mirny then claims that this second strategy is used in prokaryotes for “local” regulators … so that the transcription factor’s genomic location is nearby to the genes it will eventually regulate. Recall that in prokaryotes transcription and translation occur in rapid succession … even simultaneously. Therefore the protein is produce nearby to where it is expected to bind. Regulators with lots of DNA targets, “global” regulators, do not show these patterns.

The majority of Mirny’s talk was over work published in PNAS last year:

Kolesov, G., Wunderlich, Z., Laikova, O.N., Gelfand, M.S., Mirny, L.A. (2007). How gene order is influenced by the biophysics of transcription regulation. Proceedings of the National Academy of Sciences, 104(35), 13948-13953. DOI: 10.1073/pnas.0700672104

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2 Responses to “Biophysics of Transcriptional Regulation”

  1. son1 Says:

    How much do you think that nuclear 3d structure could play a similar role, in eukaryotes? Imagine a situation in which the chromosomes are packed into the nucleus in such a way that certain parts of particular chromosomes are near certain convenient pores in the nucleus — particular factors might be shuttled through particular pores, even, and would be much more likely to find the binding sites that are physically close to those points-of-entry.

    You’d be in this crazy situation where regulation could occur simply be re-arranging the chromosomes within the nucleus itself. (!)

    [On the other hand, maybe differential binding of transcription factors to “equivalent” sequence elements could give you rough distance measurements, sort of genomic mile-markers, of the location of each binding event from the nuclear port of entry for that factor…]

  2. ellen Says:

    I had a related question about cell differentiation in eukariotes.how does proximity in DNA location relate to cell differentiation? Are genes which turn on in bundles to make a cell of a certain type, typically located close to one another, so that they could be easily unpacked during development? one could imagine that the hierarchical structure of differentiation can be reflected somehow in the position on the genome. Any evidence for that?


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