The Dynamic Epigenome in Cell Fate Transitions in Health and Disease

Understanding the ‘epigenetic’ processes that regulate reprograming and differentiation of stem cells has gained importance in both regenerative medicine as well as many diseases. We focus on DNA methylation, an epigenetic mark classically associated with long-term gene silencing, and its loss i.e. DNA demethylation. Recent findings have demonstrated that DNA demethylation is quite dynamic and can occur in a ‘active’ manner, without DNA replication or cell proliferation, via the enzymatic activity of the Ten-eleven-translocation (TET) family of proteins, consisting of three known members: TET1, 2 and 3 (reviewed in Bhutani et al., Cell 2011). The TET proteins oxidize existing methylation marks (5mC) to hydroxymethylcytosine (5hmC) and further derivatives (5fC and 5caC) that can lead to loss of 5mC. Additionally, 5hmC is stable and acts as an epigenetic mark by itself. Osteoarthritis (OA) is a multifactorial disease characterized by joint dysfunction and cartilage degeneration that affects 40% of the elderly population. Clinical management of OA is largely limited to pain management or an eventual total joint replacement. Various genes render susceptibility to OA, however there is not a single consensus genetic basis. Our recent analyses of normal and OA knee cartilage revealed a remarkable increase in the global 5-hydroxymethylated DNA cytosine (5hmC) levels in OA (Taylor et al. 2014 Arth. & Rheum.). Genome-wide mapping of differentially hydroxymethylated regions (DhMRs) showed a striking gain of 5hmC in gene bodies of 50% of known OA genes, suggesting a regulatory role for 5hmC dynamics in modulating OA gene expression (Taylor et al. 2015 Arth. & Rheum). 5hmC and its further modified forms (5fC and 5caC) are generated by the Ten-eleven-translocation (TET) family of proteins consisting of TET 1, 2 and 3. Although a critical role for TET proteins has emerged in cancer, the mechanisms by which these enzymes contribute to OA are largely unknown. To address the role of TET1 in OA, we have compared surgical induction and development of OA by destabilization of the medial meniscus (DMM) in wild-type (Tet1^+/+) and Tet1 knockout mice (Tet1^-/-). Remarkably, loss of TET1 protects against OA development as TET1 knockout mice exhibit a reduction in OA severity. The goal now is to elucidate the precise target genes regulated by TET1 and 5hmC in OA onset and progression for a potential therapeutic benefit. In addition, mapping early epigenetic changes in OA can potentially lead to early biomarkers for OA. Early detection of OA has remained challenging and overcoming this difficulty can help devise early interventions for the disease before the widespread joint damage takes over. Our epigenetic studies therefore have the potential to provide novel insights into OA pathogenesis as well as therapeutic strategies.