Chromatin modification and disease.

“Physicians consider that when they have discovered the cause of disease, they have also discovered the method of treating it.” Cicero, Tusculan Disputations, III.x.23. In the last few years, the exciting realisation in the field of gene regulation is that transcription factors can function by recruiting large, multiprotein complexes which mediate several types of chromatin modification and remodelling events that alter the structure of chromatin. Chromatin structure changes include posttranslational modifications of histones, DNA methylation, remodelling of the chromatin, and the maintenance of a heterochromatic or euchromatic state. Most of these events are brought about by enzymatic mechanisms. In general, the catalytic subunits are only one component of the complexes, with the distribution and localisation of the structural changes dependent on targeting components. Many of the catalytic components (sometimes called coactivators and corepressors) interact with the activator and repressor proteins that mediate the actual process of transcriptional regulation. Transcriptional dysregulation can therefore arise from mutations that cause the loss or perturbation of chromatin modification or remodelling, which are now known to have an important role in the pathogenesis of cancer and other genetic diseases. Some of the proteins that mediate these events are therefore novel molecular targets for future treatments. In eukaryotes, DNA is packaged by histone proteins into nucleosomes, the fundamental repeating structural unit of chromatin. The nucleosomal core particle consists of an octomeric complex of core histones (two each of H2A, H2B, H3, and H4) around which 147 bp of DNA is wrapped in 1.65 turns of a left handed superhelix. The minor and major grooves of adjacent turns of the DNA superhelix line up and form channels through which the histone N-termini domains protrude from the core. These regions are in the form of “tails” that appear to lack secondary structure and are subject to various enzyme catalysed, post-translational modifications which aVect their charge and can influence the degree of chromatin compaction. The tightness with which DNA is packaged into chromatin will limit the binding and function of proteins that mediate transcriptional regulation, and this will therefore influence the transcriptional competence of any given gene in such a chromatin environment. 4 Covalent post-translational acetylation and deacetylation of specific lysine residues in the histone N-termini is one of the most widely studied chromatin modifications. In the past four years there have been rapid advances in identifying the enzymes and multiprotein complexes that bring about histone acetylation (the family of histone acetyltransferases or HAT coactivators) and deacetylation (the histone deacetylases or HDAC corepressors). This review will focus on some of the clinical aspects of this recent work on acetylation and the intimate connection that it is now known to have with the methylation of cytosine residues in DNA. A third type of chromatin remodelling is the direct physical repositioning or disruption of nucleosomes mediated by a family of DNA dependent ATPases. The connection between this latter type of remodelling and either histone acetylation or DNA methylation is complicated, but progress is being made. For example, the NuRD multiprotein complex (see below, fig 1C) contains histone deacetylase and chromatin remodelling activities, as well as the methyl DNA binding protein MBD3, which suggests that a profound interplay between these modifications is required during gene regulation. Therefore, it is probable that a particular pathogenesis may be caused by defects in more than one type of chromatin modification. Relevant pathologies and syndromes are discussed in following sections and are summarised in table 1.