Nucleosome Mediated Transcription Regulation

Applet Help!

Top panel

Fast Update / Animation: The button in the top right corner, gives the option to either gather statistics fast or to view the recruitment and nucleosome updates as a little sequence of events. The feeder is located on the left site and the promotor is on the right site. When the Nucleosome the promotor sits on is either methylated or unmodified, the promotor will have a black X over it, indicating that its inactive.

Bottom panel

The Applet continues to run through a sequence of σ gathering statistics.

The left plot shows the probability distribution for each of theses σ's, with the distribution for the current value highlighted in red.

The right plot shows the average number of A's for each σ. The simulation for any σ can be accessed by pressing the corresponding square in this plot. (Not active before the first round of σ's is completed).

The control buttons gives the possibility to change the system size N, the recruitment to noise ratio F and the asymmetry μ. The asymmetry can either work on the recruitment mechanism or the noise, an option thats given by the last button.

Philosophy

Expression of genes are regulated by transcription factors (TF) that typically binds to certain operator sites upstream of the promoter for the gene. Procaryotic transcription initiation are mostly regulated through a direct contact between the transcription factor a RNA polymeraze (RNAP) at the promoter. For eucaryotes, the multiplicity of regulatory sites on typical genes and the ubiguetous cooperativity of eucaryotic gene regulation suggest indirect actions of transcription factors. In particular, the fact that upstream regulatory regions of genes often includes tenth of kilo bases of DNA, many operator sites and modulation by multiple transcription factors raises the question on how so many proteins bound on such a wide region of DNA can influence the 20-40nm RNAP-mediator complex on the promoter region.

In the applet we investigate how a transcription factor that recruit histone modyfying enzymes may use these to influence the overall state of nucleosomes in the region where the gene is embedded. With varying strength of the TF mediated recruitment, one easily obtain a sharp response on the average nucleosome state, and thereby for the activity of the promoter in region regulated by the transcription factor.
Sharp respoonse is obtained for high level of internal positive feedback relative to random nuccleosome modiification events. Notice that sharp response is associated to bistability in the transition region.

The basic Algorithm is similar to that introduced in [1], with an added asymmetry μ and the regulation by TF σ. The steps are shown in the figure below.

[1] I. B. Dodd, M. A. Micheelsen, K. Sneppen and G. Thon. (2007)
Theoretical Analysis of Epigenetic Cell Memory by Nucleosome Modification
Cell, 129, p 813-822.
See the Live Model on this work

[2] K. Sneppen, M. A. Micheelsen, I. B. Dodd. (2008)
Ultrasensitive gene regulation by positive feedback loops in nucleosome modification
Molecular systems Biology, 4, p 182