From adjacent activation in Escherichia coli and DNA cyclization to eukaryotic enhancers: the elements of a puzzle

Abstract

Deoxyribonucleic acid cyclization, Escherichia coli lac repressor binding to two spaced lac operators and repression enhancement can be successfully used for a better understanding of the conditions required for interaction between eukaryotic enhancers and the machinery of transcription initiation. Chronologically, the DNA looping model has first accounted for the properties initially defining enhancers, i.e., independence of action with distance or orientation with respect to the start of transcription. It has also predicted enhancer activity or its disruption at short distance (site orientation, alignment between promoter and enhancer sites), with high-order complexes of protein, or with transcription factor concentrations close or different from the wild-type situation. In another step, histones have been introduced into the model to further adapt it to eukaryotes. They in fact favor DNA cyclization in vitro. The resulting DNA compaction might explain the difference counted in base pairs in the distance of action between eukaryotic transcription enhancers and prokaryotic repression enhancers. The lac looping system provides a potential tool for analysis of this discrepancy and of chromatin state directly in situ. Furthermore, as predicted by the model, the contribution of operators O2 and O3 to repression of the lac operon clearly depends on the lac repressor level in the cell and is prevented in strains overproducing lac repressor. By extension, gene regulation especially that linked to cell fate, should also depend on transcription factor levels, providing a potential tool for cellular therapy. In parallel, a new function of the O1–O3 loop completes the picture of lac repression. The O1–O3 loop would at the same time ensure high efficiency of repression, inducibility through the low-affinity sites and limitation of the level of repressor through self-repression of the lac repressor. Last, the DNA looping model can be successfully adapted to the enhancer auxiliary elements known as insulators.

p53 binding to human genome: crowd control navigation in chromatin context

“…Because of motifs degeneracy, numerous DNA binding sites, besides the “functional” ones, are present for a given DNA binding protein (p53 including). Thus, “functionality” is specified by additional means, such as clustering of binding sites, combinatorial and cooperative binding ( Kadonaga, 2004 ), and three-dimensional organization of the chromatin ( Lieberman-Aiden et al, 2009 ; Edelman and Fraser, 2012 ; Amouyal, 2014 ). The point is, why on the first place, eukaryotic DNA binding proteins evolved to have degenerate motifs, meaning promiscuous binding to the genome, and requiring additional means to specify functionality?…”

Towards the Discovery of Oligonucleotide Cross-Linking Agents

“…Lambda repressor is a gene regulatory protein that binds to target DNA by hydrogen bond formation and regulates a gene synthesis. [48,50] The interaction B depicts the association of histones with DNA. This interaction checks the supply of transcription factor and makes gene expression slow.…”