Abstract
In its widest sense, the term epigenetics describes a range of mechanisms in genome function that do not solely result from the DNA sequence itself. These mechanisms comprise DNA and chromatin modifications and their associated systems, as well as the noncoding RNA machinery. The epigenetic apparatus is essential for controlling normal development and homeostasis, and also provides a means for the organism to integrate and react upon environmental cues. A multitude of functional studies as well as systematic genome-wide mapping of epigenetic marks and chromatin modifiers reveal the importance of epigenomic mechanisms in human pathologies, including inflammatory conditions and musculoskeletal disease such as rheumatoid arthritis. Collectively, these studies pave the way to identify possible novel therapeutic intervention points and to investigate the utility of drugs that interfere with epigenetic signalling not only in cancer, but possibly also in inflammatory and autoimmune diseases.
Highlights
The field of epigenetics has rapidly evolved over the last decades – a quick literature survey shows 18 PubMed entries for 1975 to 1995, >400 entries for the following 10 years and >2,000 entries from 2006 to 2010
The rise of epigenetics highlights the maturation of an area, created half a century ago, which is still associated with a somewhat blurred definition
The epigenetics field is anticipated to contribute to understanding of the complexities of genetic regulation, cellular differentiation, embryology, aging and disease and to allow one to systematically explore novel therapeutic avenues, leading to personalised medicine
Summary
The field of epigenetics has rapidly evolved over the last decades – a quick literature survey shows 18 PubMed entries for 1975 to 1995, >400 entries for the following 10 years and >2,000 entries from 2006 to 2010. Once established in differentiated cells, DNA methylation is considered stable; recent studies reveal that it appears to be subject to demethylation (that is, reversal of biological effect) in specific instances, involving several incompletely characterised candidate mechanisms (that is, methylcytosine hydroxylation, DNA glycosylation, base excision repair and deaminases), all of which have been shown to play important roles in genome biology and disease (reviewed in [24]). Histone lysine methyltransferases catalyse the S-adenosylmethionine-dependent methylation of lysine residues in histone and other chromatin proteins in a sequence and methylation state-specific manner – these marks can be removed by the recently discovered lysine demethylases (formerly known as histone demethylases) in establishing histone methylation modifications These opposing activities constitute a switch mechanism between functional states – for example, changing between the acetylated (active transcription) and trimethylated (repressed) state of H3K9 must involve the eraser activities described above. HDAC inhibitors (for example, MS-275, Trichostatin A) have shown therapeutic activity in inhibition of synovial fibroblast proliferation [77,78] as well as in stress-induced osteoarthritis models – for example, by inhibiting cyclic tensile strain-induced expression of RUNX-2 and ADAMTS-5 via the inhibition of mitogen-activated protein kinase pathway activation in human chondrocytes [89,90]
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