Chromatin Modification and Disease

J Med Genet 2000;37:905–915 905 Chromatin modification and disease J Med Genet: first published as 10.1136/jmg.37.12.905 on 1 December 2000. Downloaded from Colin A Johnson “Physicians consider that when they have discov- plexes that bring about histone acetylation (the ered the cause of disease, they have also discovered family of histone acetyltransferases or HAT the method of treating it.” Cicero, Tusculan Dis- coactivators) and deacetylation (the histone putations, III.x.23. deacetylases or HDAC corepressors). This In the last few years, the exciting realisation review will focus on some of the clinical aspects in the field of gene regulation is that transcrip- of this recent work on acetylation and the inti- tion factors can function by recruiting large, mate connection that it is now known to have multiprotein complexes which mediate several with the methylation of cytosine residues in types of chromatin modification and remodel- DNA. A third type of chromatin remodelling is ling events that alter the structure of chroma- the direct physical repositioning or disruption tin. Chromatin structure changes include post- of nucleosomes mediated by a family of DNA translational modifications of histones, DNA dependent ATPases. The connection between methylation, remodelling of the chromatin, and this latter type of remodelling and either the maintenance of a heterochromatic or histone acetylation or DNA methylation is euchromatic state. Most of these events are complicated, but progress is being made. For brought about by enzymatic mechanisms. In example, the NuRD multiprotein complex (see general, the catalytic subunits are only one below, fig 1C) contains histone deacetylase and component of the complexes, with the distribu- chromatin remodelling activities, as well as the tion and localisation of the structural changes methyl DNA binding protein MBD3, which dependent on targeting components. Many of suggests that a profound interplay between the catalytic components (sometimes called these modifications is required during gene coactivators and corepressors) interact with the regulation. Therefore, it is probable that a par- activator and repressor proteins that mediate ticular pathogenesis may be caused by defects the actual process of transcriptional regulation. in more than one type of chromatin modifica- Transcriptional dysregulation can therefore tion. Relevant pathologies and syndromes are arise from mutations that cause the loss or per- discussed in following sections and are summa- turbation of chromatin modification or remod- rised in table 1. elling, which are now known to have an impor- tant role in the pathogenesis of cancer and Histone acetylation, protein acetylation, other genetic diseases. Some of the proteins and gene regulation http://jmg.bmj.com/ that mediate these events are therefore novel HISTONE DEACETYLASES AND COREPRESSOR molecular targets for future treatments. COMPLEXES In eukaryotes, DNA is packaged by histone Deacetylation of histones is, in general, associ- proteins into nucleosomes, the fundamental ated with repression of gene transcription, pre- 1 repeating structural unit of chromatin. The sumably because the highly positively charged nucleosomal core particle consists of an N-terminal tails of the core histones can now octomeric complex of core histones (two each interact with DNA on the nucleosome surface of H2A, H2B, H3, and H4) around which 147 56 and in the linker DNA. In addition, the posi- on September 27, 2021 by guest. Protected copyright. bp of DNA is wrapped in 1.65 turns of a left tively charged lysines in the H4 tail may inter- handed superhelix.2 The minor and major act with the negative face of an H2A-H2B grooves of adjacent turns of the DNA superhe- dimer from a neighbouring nucleosome,7 and lix line up and form channels through which hence bring about further compaction of the the histone N-termini domains protrude from chromatin. Deacetylation is brought about by the core. These regions are in the form of the action of the histone deacetylases “tails” that appear to lack secondary structure3 (HDACs), which would therefore enhance and are subject to various enzyme catalysed, histone-histone interactions by maintaining the post-translational modifications which aVect positively charged (unmodified) state of lysines their charge and can influence the degree of in the histone tails. HDACs are now known to chromatin compaction. The tightness with be corepressor components of many multipro- which DNA is packaged into chromatin will tein complexes that modify and remodel chro- limit the binding and function of proteins that matin. Chromatin and Gene mediate transcriptional regulation, and this will Targeting of complexes containing HDAC1 Expression Group, therefore influence the transcriptional compe- and HDAC2 is achieved by the interaction of Department of tence of any given gene in such a chromatin the repressor proteins Sin3A, Sin3B,8 and Anatomy, University of environment.24 9 Birmingham, other Sin3 associated proteins (SAPs) in a Birmingham B15 2TT, Covalent post-translational acetylation and large multiprotein complex that comprises at UK deacetylation of specific lysine residues in the least seven subunits10 (fig 1A). The mammalian histone N-termini is one of the most widely Sin3 complex mediates repression for an Correspondence to: studied chromatin modifications. In the past extensive and ever growing list of transcrip- Dr Johnson, 81011 [email protected] four years there have been rapid advances in tional regulator proteins, which include identifying the enzymes and multiprotein com- DNA binding components such as the Mad/ www.jmedgenet.com 906 Johnson J Med Genet: first published as 10.1136/jmg.37.12.905 on 1 December 2000. Downloaded from Figure 1 Schematic representation of multiprotein complexes that mediate chromatin modifications. Some of the known components of the complexes are shown on the left, with arrows indicating additional interactions with other proteins on the right (refer to main text for details). Histone deacetylases (HDAC) are shown in purple, components of the DNA methylation system in yellow, and ATPase/helicase that mediates chromatin remodelling in green. Other corepressor accessory proteins in the complexes (panels A-C) are shown in grey. (A) Components of the HDAC/Sin complex and known interacting proteins. (B) Additional interactions of the HDAC/Sin3 complex, mediated by the corepressors NcoR/SMRT,with unliganded nuclear receptors and leukaemogenic fusion proteins. Note that these interactions occur at low concentrations, or in the absence of the receptor ligand. (C) Components and interactions of the NuRD complex. Max heterodimer and nuclear hormone recep- appears to induce an exchange of the corepres- tors (see below, fig 1B). The members of the sor complexes containing HDACs for those Mad/Mxi1 family12 are able to replace Myc in with coactivator functions that contain histone the Myc/Max heterodimer, and can therefore acetyltransferase (HAT) activities18 19 (compare repress transcription at promoters with Myc figs 1B and 2A). consensus DNA binding sites. Mutations in the Histone deacetylases are also recruited by Sin3 interaction domains (SIDs) of Mad/Mxi1 the retinoblastoma protein pRb20 (fig 1A), the can abolish binding of the corepressors to the product of a tumour suppressor gene, and an Sin3 proteins and hence HDACs, and this cor- inhibitor of cell proliferation.21 The inhibitory relates with the abolition of transcriptional action of pRb is the result, in part, of its ability repression and anti-oncogenic activity.13 In to bind to the E2F family of DNA binding addition, transfection studies have shown that transcription factors, which results in the HDACs and Mad cooperate to repress cell sequestration of E2F and repression of E2F 14 proliferation. In a similar mechanism, the target genes during the G1 phase of the cell http://jmg.bmj.com/ transcriptional corepressor proteins N-CoR cycle.22 The interaction is mediated by the A/B (nuclear hormone receptor corepressor) and pocket domain in pRb, and it is no coincidence SMRT (silencing mediator of retinoid and thy- that the great majority of Rb mutations in roid hormone receptor) target deacetylase human tumours are located in this domain. activity to non-liganded thyroid hormone and 15–17 The pocket domain can also interact with a retinoic acid nuclear receptors and to variety of other cellular proteins, including viral antagonist bound oestrogen and progesterone transforming oncoproteins (such as E1A from 18 on September 27, 2021 by guest. Protected copyright. receptors. As discussed below, the presence of adenovirus and SV40 large T23) and histone receptor ligands, for example, retinoic acid, deacetylases (HDAC1 and HDAC2) that share the common LXCXE motif which allows interactions with pocket proteins. However, the interaction between Rb and either HDACs or viral oncoproteins appears to be competitive, and the Rb-HDAC1 interaction may be one of the intracellular targets for these transforming proteins. The Rb-HDAC interaction has been analysed by transient transfection experiments, which show that Rb and the HDACs cooperate in repressing an E2F1-driven promoter,24–26 and the repression exerted by Rb and other pocket proteins during the G1 phase of the cell Figure 2 Schematic representation of interactions mediated by histone acetyltransferases cycle27 can be reversed by treatment with (HATs). Unbroken arrows indicate known interactions of HATs with the proteins listed on the right (refer to

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