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Gene Regulation Info

Quantitative descriptions of gene regulation

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Software

/At the moment my software is distributed only to collaborators or following personal requests/


Transcription factor access to nucleosomal DNA in chromatin (dynamic programming solution)

TFnuc - calculates TF binding maps in the chromatin context including the possibility of partial nucleosome unwrapping. The initial algorithm was published early in 2012 (Teif and Rippe, 2012) and was recently extended to allow arbitrary heterotypical cooperativity between nucleosomes and TFs (Teif et al., 2013). This algorithm is based on the dynamic programming approach. Other methods to calculate protein binding maps along the DNA include the binary variable method, combinatorial method, generating function method, transfer matrix method as reviewed elsewhere (Teif and Rippe 2010; Teif and Rippe 2012). First dynamic programming algorithms for protein-DNA binding were developed in the 1970s independently by DeLisi in USA (DeLisi 1974a; DeLisi 1974b) and Gurskii and Zasedatelev in USSR (Gurskii and Zasedatelev 1978; Krylov et al. 1979) and for some time were used only by specialists interested in theoretical aspects of such models (Di Cera 1990; Di Cera and Keating 1994; Di Cera and Kong 1996). Then these methods were almost forgotten, but recently they become very popular again, particularly in the nucleosome positioning and TF binding fields (Granek and Clarke 2005; Nechipurenko et al. 2005; Hermsen et al. 2006; Segal et al. 2006; Segal et al. 2008; He et al. 2009; Laurila et al. 2009; Morozov et al. 2009; Wasson and Hartemink 2009; He et al. 2010; Hermsen et al. 2010). 

 Details of our algorithms are provided in the following publications:

  • Teif V.B., Erdel F., Beshnova D.A., Vainshtein Y., Mallm J.-P., Rippe K. (2013) Taking into account nucleosomes for predicting gene expression. Methods. | Advance Access Online | PDF |


Transcription factor access to nucleosomal DNA in chromatin (transfer matrix solution)

Matrix_Unwrap - calculates transcription factor access to nucleosomal DNA taking into account the possibility of partial DNA unwrapping from the histone core octamer.

Nucleosome, the basic repeating unit of chromatin, consists of 147 basepairs of DNA that are wrapped in almost two turns around a histone protein octamer core. Because ~3/4 of the human genomic DNA is found within nucleosomes, their position and DNA interaction is an essential determinant for the DNA access of gene-specific transcription factors and other proteins. Here, a DNA lattice model was developed for describing ligand binding in the presence of a nucleosome. The model takes into account intermediate states, in which DNA is partially unwrapped from the histone octamer. This facilitates access of transcription factors to up to 60 DNA basepairs located in the outer turn of nucleosomal DNA, while the inner DNA turn was found to be more resistant to competitive ligand binding. As deduced from quantitative comparisons with recently published experimental data, our model provides a better description than the previously used all-or-none lattice-binding model. Importantly, nucleosome-occupancy maps predicted by the nucleosome-unwrapping model also differed significantly when partial unwrapping of nucleosomal DNA was considered. In addition, large effects on the cooperative binding of transcription factors to multiple binding sites occluded by the nucleosome were apparent. These findings indicate that partial unwrapping of DNA from the histone octamer needs to be taken into account in quantitative models of gene regulation in chromatin.

Details of the algorithm are described in the following publications:

  • Teif V. B. (2007). General transfer matrix formalism to calculate DNA-protein-drug binding in gene regulation: Application to OR operator of phage lambda. Nucleic Acids Res. 35, e80. Click here to read Click here to read
  • Teif V. B. and Rippe K. (2009). Predicting nucleosome positions on the DNA: combining intrinsic affinities and remodeler activities. Nucleic Acids Res. 37, 5641-5655. | PubMed | PDF | Supplementary Materials |
  • Teif V. B., Ettig R. and Rippe K. (2010). A lattice model for transcription factor access to nucleosomal DNA. Biophys. J. 99, 2597-2607 | PDF | 

 


 DNA condensation induced by ligand binding

TwoStateDNA - Calculates ligand-induced DNA condensation in the frame of the two-state model.

In studying DNA condensation using lattice-binding approaches, we have to consider at least two coupled events: the DNA–ligand binding and DNA condensation. The "threshold degree of binding" model assumes that ligand–DNA binding is non-cooperative and does not depend on DNA compaction.In this model, DNA condenses when the degree of binding reaches a certain threshold value. On the other hand, the "two-state" models assume that DNA may be in two states, starting or condensed, and the transition between the two states is governed by different modes of ligand binding to each state. In the case of non-specific reversible binding, DNA condensation/decondensation may even be described analytically.

The notation is described in the following article:

Teif V. B. Ligand-induced DNA condensation: choosing the model. Biophys. J. 89, 2574-2587 (2005). | Free full text | Download program |

 


Multiprotein binding in gene regulation

Matrix_CSL - calculates multiprotein assembly on the DNA using the transfer matrix formalism. This method considers site-specificity, contact- and long-range protein-protein interactions, competitions, multilayer binding and DNA loops as shown in the figure. Recently, we have added to this toolbox advanced models such as partial nucleosome unwrapping upon interaction with transcription factors, which are availavle in the frame of Matrix_Unwrap. Details for Matrix_SCL provided in the following article:

Teif V. B. General transfer matrix formalism to calculate DNA–protein–drug binding in gene regulation: application to OR operator of phage lambda. Nucleic Acids Res. 35, e80 (2007). | Free full text | Download program |

 


Unstructured protein binding to a multicomponent membrane

Matrix_MARCKS - Calculates sequence-specific binding of an unstructured polymer to a fluid multicomponent membrane in the frame of the formalism described in the following article:

Teif V.B., Harries D., Lando D. Y. and Ben-Shaul A. (2008). Matrix formalism for site-specific binding of unstructured proteins to multicomponent lipid membranes. J. Pept. Sci. 14, 368-373. | Article PDF | Download program |