Nucleosome positioning in promoters: Significance and open questions

Introduction The structure and function of the human genome are so intricately intertwined that understanding gene regulation necessitates viewing the genome as a dynamic three-dimensional entity which controls its own information content. The spatial organization of DNA into chromatin provides a critical layer of tissue-specific instructions for regulating the accessibility and distal interactions of genomic loci. Even though recent high-throughput studies have begun to unravel how chromatin structure affects transcriptional regulation, our understanding still remains very rudimentary. Several puzzling issues persist in the literature, and different interpretations have now gained strong supporters who propound conflicting views. This chapter highlights some of the computational and biological issues that may prove beneficial for scientists to bear in mind when entering the study of epigenetics. The fundamental repeating subunits of chromatin are the nucleosomes which consist of 146 base pairs (bp) of DNA wrapping around histone octamers in 1.65 left-handed superhelical turns (Luger and Richmond, 1998). Chromatin is organized in a hierarchical order, the first level of which is represented by a linear array of nucleosomes, with roughly one nucleosome every 200 bp. The beads-on-a-string configuration is believed to be folded into a fiber of 30 nm diameter in transcriptionally repressed heterochromatin regions (Robinson and Rhodes, 2006; Routh et al., 2008), and the fiber further folds into a highly condensed form during metaphase. The precise structure of the 30-nm chromatin fiber and beyond still remains unknown. It is believed that global high-order chromatin structure requires covalent modifications of histone N-terminal tails, such as H3K9 and H3K27 trimethylation; proteins that recognize such modifications and that interact with each other may then facilitate the dense compaction of chromatin.