Although the genetic messages in DNA are stored in a linear sequence of base pairs, the genomes of living species do not function in a linear fashion. Gene expression is regulated by DNA elements that often lie far apart along the genomic sequence but come close together during genetic processing. The intervening residues form loops, which are further organized in the nuclei of eukaryotic cells into nucleosomes. Indeed, the DNA loops formed by eukaryotic proteins along the strings of nucleosomes in chromatin can be extremely long. For instance, they can be comprised of up to hundreds of thousands of base pairs in HeLa cells. How proteins communicate across these distances has long been a mystery.
Two recent papers from Professor Wilma K. Olson, postdoctoral researchers Nicolas Clauvelin and Andrew V. Colasanti, and graduate students Gautam Singh and Guohui Zheng — all from the Rutgers Department of Chemistry and Chemical Biology and the BioMaPS Institute for Quantitative Biology, and their collaborators — the research teams of Anirvan Sengupta in the Rutgers Department of Physics and Astronomy and Vasily M. Studitsky at the Robert Wood Johnson Medical School — provide a first step toward the solution of this problem. Their studies show that the structure and dynamics of chromatin are highly sensitive to changes in the chemical environment. The nucleosomes facilitate distant communication between DNA-bound regulatory proteins, and the positively charged ‘tails’ of the histone proteins are critical for these effects. Their results hint of ways in which chemical modifications of the histone proteins, so-called epigenetic markers, might affect cellular processes. The new work shows how one can investigate these processes at a three-dimensional level and can potentially connect nucleosome structure and positioning, and chromatin folding and fluctuations to function. The results also suggest that long-range communication constitutes a novel, early-regulated step in gene expression and identify the histone tails and their modifications as potential targets for this regulation. Since misregulation of enhancer action is associated with numerous human diseases, the combination of computation and experiment could uncover new target(s) for drug development.
Olga I. Kulaeva, Guohui Zheng, Yury S. Polikanov, Andrew V. Colasanti, Nicolas Clauvelin, Swagatam Mukhopadhyay, Anirvan Sengupta, Vasily M.Studitsky, Wilma K. Olson (2012) Internucleosomal Interactions Mediated by Histone Tails Allow Distant Communication in Chromatin. J Biol Chem 287(24) 20248-20257. doi: 10.1074/jbc.M111.333104
Wilma K. Olson, Nicolas Clauvelin, Andrew V. Colasanti, Gautam Singh, Guohui Zheng. (2012) Insights into Gene Expression and Packaging from Computer Simulations. Biophys Revs 4(3), 171-178. doi: 10.1007/s12551-012-0093-8