Gene Regulation Info

Quantitative approaches for gene regulation

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Epigenetic regulation in chromatin

In eukaryotes, the DNA-binding of many protein factors involved in processes like transcription, replication, repair and recombination is dependent on the chromatin organization. In particular the wrapping of DNA around the histone octamer complex has long been recognized as a mechanism to make DNA sequences inaccessible for the binding of other proteins. Accordingly, changes of nucleosome positions at promoter and enhancer regions have been shown to directly affect gene expression. Nucleosome positions are determined by three major contributions: the intrinsic binding affinity of the histone octamer depends on the DNA sequence, competitive/cooperative binding of other protein factors, and active translocation by ATP-dependent remodeling complexes. The challenge is to take into accout all these contributions and predict nucleosome repositioning in gene regulation in vivo (Teif & Rippe, NAR 2009; Teif and Rippe, JPCM 2010).

Here I am collecting annotated links of nuclesome positionining data and tools online.

Last Updated on Wednesday, 11 August 2010 12:09
 

Signal transduction

A systematic lattice methodology developed to calculate DNA-protein binding in gene regulation is also applicable to study signal transduction on a membrane. In a project with Avinoam Ben-Shaul and Daniel Harries, we have developed a model for an unstructured protein MARCKS, which binds a multicomponent lipid membrane, sequesters lipids-precursors of second messengers, and unbinds and releases them upon phosphorylation (Teif et al., 2008; Teif et al., 2009). This model descibes biding of an unstructured signal protein/peptide, but may be also extended to include multiprotein assembly on the membrane. This could help in studies of, for example, the membrane-cytoskeleton attachment and its regulation by binding of small ligands such as ATP and Ca2+. Multilayer matrix models may be also applicable to lipid-templated amyloid-type protein fibril formation.

Last Updated on Sunday, 04 April 2010 19:30
 

DNA-protein binding in chromatin

 

Although binding events are very complex, gene regulation is still centered on the DNA or RNA, which provides a one-dimensional template for protein binding. The general idea behind one-dimensional lattice models is that the DNA is divided into the elementary units and described by multiple states associated with each of the unit (bound/unbound). The elementary DNA units are usually taken as nucleotides (A, T, G, C) or base pairs. Basic features of DNA-protein-drug binding encountered in gene regulation include site specificity determined by the DNA sequence; binding site overlapping; competitions between different protein types or different binding modes; interactions between proteins bound to the DNA; multilayer binding (when a protein bound to the DNA presents a lattice for the next-layer binding of other proteins), and protein-assisted DNA looping (Teif, NAR 2007; Teif, BJ 2010). In chromatin, additional complex elements such as nucleosomes, remodelers and higher-order chromatin structures should be taken into account (Teif and Rippe, NAR 2009, Teif and Rippe, JPCM 2010).

I am maintaining here an annotated list of online resources where the parameters may be obtained for calculations

Last Updated on Wednesday, 11 August 2010 13:05
 

Gene Regulation Functions

Biological systems communicate through networks of interacting gene expression modules. The elementary genetic module is the smallest group of cis-acting regulatory sites, which may be mechanistically decoupled from the entire system and still retain its function.

The output of such modules ("black boxes") can be uniquely determined by gene regulatory functions, where input variables are the concentrations of regulatory proteins and the output is the activity of a promoter:

See details in Teif V. B. (2010). Predicting gene-regulation functions: Lessons from temperate bacteriophages. Biophys. J. 98, 1247-1256

Last Updated on Friday, 13 August 2010 20:11 Read more...
 

DNA condensation

DNA condensation scheme

DNA is stored in vivo in a highly compact, so-called condensed phase, where gene regulatory processes are governed by the intricate interplay between different states of DNA compaction. This direction is important for fundamental questions such the origin of life and epigenetic gene regulation and may have pharmaceutical applications in gene therapy. The systems involving condensed DNA are very crowded and often have surprising properties, which one would not predict from classical concepts of dilute solutions. Recent developments in the study of DNA condensation have been associated with approaches coming from biochemistry, electrostatics, statistical mechanics and quantitative biology. Different aspects of condensed DNA behavior revealed by these approaches are linked to each other, but the links are often hidden in the bulk of experimental and theoretical details.

See details in our recent review: Teif V.B., Bohinc K. (2010) Prog Biophys Mol Biol.

Last Updated on Saturday, 07 August 2010 20:22