Epigenetics in inflammatory rheumatic diseases

Abstract

Inflammatory rheumatic disorders, such as rheumatoid arthritis (RA) and connective tissue diseases, are characterized by chronic inflammation that generally can be overcome by lifelong administration of immunosuppressive therapies. In most of these diseases, factors of genetic predisposition have been described, in particular the influence of distinct HLA haplotypes. In addition, environmental factors, including nutrition, infection, and exposure to sunlight, have been postulated as disease-driving agents. It is, however, unclear how genetic susceptibility in concert with the factors mentioned lead to the development of disease in one individual but not in another. The successful accomplishment of the Human Genome Project, which has yielded sequences for !25,000 identified human genes, presents a challenge to biomolecular research, since most of the identified genes code for biologic functions that have yet to be discovered. The functional characterization of these genes in normal physiologic processes as well as in the pathogenesis of diseases, a concept generally referred to as functional genomics (1), remains the main issue for biomedical research in the coming years. Within the nucleus of a human cell, the DNA sequence contains !3 billion basepairs, covering most of the nonheterochromatic portions of the genome. The low number of genes detected by the Human Genome Project is, however, most surprising. Moreover, between humans and chimpanzees, a remarkable genetic similarity of nearly 99% has been reported, thus highlighting the importance of distinguishing areas of the genome that would define genetic changes unique to humans (2). The low number of genes reflects the functional impact of posttranscriptional as well as posttranslational modifications and of epigenetic alterations in creating proteome diversity. Epigenetic alterations comprise heritable modifications of the DNA without any change in the base sequence of the genetic code per se. Two major groups of epigenetic alterations have been identified, i.e., DNA methylation and histone modifications. Changes to DNA or alternative splicing of messenger RNA (mRNA) transcripts has a strong impact on proteome complexity, and thus the utility of genomic information is somewhat restricted by the lack of precision in predicting genes, gene structures, and alternative splices (3,4). Epigenetic alterations can be inherited; however, changes can occur over the full span of a human life. When analyzing the epigenome (the genome-wide distribution of epigenetic alterations) in homozygous twins, Farga et al found a very similar epigenetic pattern in younger twin pairs, whereas older twin pairs showed several differences in the pattern of histone acetylation and DNA methylation, particularly in those whose lifestyles were not shared (5). Currently, the epigenome is not measured systematically, and epigenetic changes have not been assessed within the Human Genome Project. For several illnesses, however, evidence indicates that they are linked to specific epigenetic processes and variations, which might provide an explanation for the late onset and strong age dependency of some diseases or the progressive nature of many common diseases (6). Moreover, it is likely that epigenetic alterations underpin the role of environmental factors in the pathogenesis of diseases in genetically susceptible individuals, and thus might broaden the scope of design of new therapeutic strategies. In this review article, we focus on the emerging concepts of epigenetics (summarized in Figure 1) as they apply to inflammatory rheumatic diseases.