Dynamic regulation of epigenetic demethylation by oxygen availability and cellular redox.

The chromatin structure of the mammalian genome must facilitate both precisely-controlled DNA replication together with tightly-regulated gene transcription. This necessarily involves complex mechanisms and processes which remain poorly understood. It has long been recognised that the epigenetic landscape becomes established during embryonic development and acts to specify and determine cell fate. In addition, the chromatin structure is highly dynamic and allows for both cellular reprogramming and homeostatic modulation of cell function. In this respect, the functions of epigenetic "erasers", which act to remove covalently-linked epigenetic modifications from DNA and histones are critical. The enzymatic activities of the TET and JmjC protein families have been identified as demethylases which act to remove methyl groups from DNA and histones, respectively. Further, they are characterised as members of the Fe(II)- and 2-oxoglutarate-dependent dioxygenase superfamily. This provides the intriguing possibility that their enzymatic activities may be modulated by cellular metabolism, oxygen availability and redox-based mechanisms, all of which are likely to display dynamic cell- and tissue-specific patterns of flux. Here we discuss the current evidence for such [O2]- and redox-dependent regulation of the TET and Jmjc demethylases and the potential physiological and pathophysiological functional consequences of such regulation.