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Histone acetylation is an important post-translational modification, both for histone and non-histone proteins, and has a comparable impact to phosphorylation on the regulation of cellular processes. Within epigenetics, histone acetylation is an integral mechanism for decreasing chromatin condensation, thereby facilitating gene transcription, but an equally important mechanism is the removal of acetyl groups through the actions of histone deacetylases (HDACs). HDACs can be divided into two groups termed group I and group II; group I, which is further divided into classes I, II and IV, contains zinc-dependent amidohydrolases whereas group II enzymes, also known as class III or SIRTs, are reliant upon nicotinamide adenine dinucleotide (NAD) as a co-factor.
Histone phosphatases can target either phosphorylated serine, threonine or tyrosine residues on histone proteins. Protein Ser/Thr phosphatases PP1, PP2A and PP4, amongst others, have been reported to dephosphorylate histone proteins. For example, the catalytic subunit of PP2A colocalizes with phosphorylated H2AX, a phosphorylated sequence variant of histone protein H2A that is rapidly concentrated within chromatin domains flanking DNA double-strand breaks. Phosphorylated H2AX acts as a docking site for DNA repair proteins, and is released from chromatin once double-strand breaks have been rejoined; this mechanism is thought to involve PP2A.
The removal of ubiquitin groups from histone lysine residues is catalyzed by proteases known as deubiquitinating enzymes (DUBs). These can be further categorized into groups including ubiquitin-specific proteases (USPs) and Jab1/MPN domain-associated metalloisopeptidase (JAMM) domain proteins. Both USP and JAMM family members have been shown to target histone proteins H2A and H2B, where they regulate transcription, DNA repair, gene expression and cell cycle progression. Compared to other histone modifications, the functions of histone ubiquitinaton are less well understood, yet increasing evidence points to an important role for this epigenetic modification in the DNA damage response.
The first histone demethylase to be discovered was lysine-specific demethylase 1 (LSD1), also known as KDM1. LSD1 contains an amino oxidase domain which binds the co-factor, flavin adenine dinucleotide (FAD), crucial for demethylation. A further family of lysine demethylases have since be identified, termed Jumonji C domain-containing demethylases (JMJD). The demethylases do not require FAD as a co-factor but instead are dependent on Fe2+/2-oxoglutarate (2-OG) for catalysis. As yet, only one enzyme with arginine demethylase activity has been identified, JMJD6, which is a 2-OG-dependent JmjC demethylase.
In contrast to the well-defined mechanisms of the removal of epigenetic marks from histones, the mechanism by which methyl groups are removed from nucleotides remains poorly understood. What is known, however, is that DNA demethylation can occur both actively and passively. Passive DNA demethylation involves the failure of maintenance DNMTs to methylate newly synthesized DNA strands during mitosis, whilst the molecular machinery that catalyzes active DNA demethylation occurs is yet to be elucidated. Since demethylation of DNA is crucial for processes such as epigenetic reprogramming in germ cells, further research into the mechanisms of active DNA demethylation may identify novel targets in stem cell research.