br Conflict of interest statement br References and

Conflict of interest statement
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:
Acknowledgements We thank Urann Chan for assistance with the figures. This work was supported in part by National Institutes of Health grant 1R01NS098804 (A.E.W.).
Introduction The first level of coiling of DNA in the nucleus is controlled by the binding of a complex of histone proteins (the nucleosome) to segments of DNA, which is in turn determined by the presence or absence of specific post-translational modifications to the histone proteins. The presence of nucleosomes on a segment of DNA reduces accessibility of that DNA to RNA polymerase and the DNA is unlikely to be transcribed (reviewed by [1]). Adding or removing histone modifications can determine whether a gene is expressed. A key modification which is associated with nucleosome binding is trimethylation of the lysine at position 27 in histone 3 (H3K27me3). This is a repressive mark, applied by EHop-016 receptor of the histone methyltransferase family, which restricts transcription [2,3]. Release of this repressive mark requires the activity of histone demethylases, particularly the enzymes lysine demethylase 6A (KDM6A; also known as ubiquitously transcribed X chromosome tetratricopeptide repeat protein, UTX; OMIM#300128) and lysine demethylase 6B (KDM6B; also known as Jumonji domain containing protein 3, JMJD3; OMIM#611577) [[4], [5], [6]]. These proteins are characterised by the presence of a Jumonji C (JmjC) catalytic domain. The gene encoding a third family member, ubiquitously transcribed Y chromosome tetratricopeptide repeat protein (UTY; also known as KDM6C; OMIM#400009) [7], was thought to be an inactive degenerate form of the KDM6A gene with no functional activity but recent studies suggest it retains some residual catalytic function [8,9] and may also be involved in methylation-independent activities [10], as outlined in Section 2. The KDM6A gene is located on the X chromosome in eutherian mammals [11]. Although not located in the pseudoautosomal region, KDM6A escapes X-inactivation [12,13] and its level of expression reflects the number of X chromosomes [14]. Eutherian females have higher levels of this protein and its mRNA than eutherian males [13,15]. However, eutherian males also carry UTY [16], the homologue of KDM6A on the Y chromosome, and its expression level correlates with the number of Y chromosomes [14]. X chromosome genes with a Y chromosome paralogue generally have a role in transcription, translation and nucleic acid binding [17] and hence are central to regulation of gene expression during development, immune function, cell proliferation and differentiation and tumorigenesis. Here we review the function, expression and evolution of the KDM6A and UTY genes and highlight the functional similarity of the two proteins.
Functions of KDM6A and UTY KDM6A functions both through its demethylase activity [5,18] and through a structural role which may be mediated by the protein binding capacity of the tetratricopeptide repeats (TPRs) [4,19] [20] (Section 3). These functions can be distinguished through use of catalytically inactive versions of the protein or through the use of demethylase inhibitors. Human UTY has reduced catalytic activity [9] but retains the protein binding capacity of KDM6A.
Evolutionary analysis of H3K27me3 demethylases KDM6A and UTY The three H3K27 demethylases contain a JmjC domain near the C terminus (Fig. 1A). The JmjC domain is found in a large family of proteins present across vertebrates and invertebrates. The KDM proteins form a subgroup of the enzyme family of 2-OG- and Fe(II)-dependent oxygenases which regulate transcription and/or chromatin structure, many through histone demethylation (Section 2) [18]. KDM6A and UTY also carry a number of tetratricopeptide repeats (TPRs) (Fig. 1A) which are important for protein-protein interactions and the assembly of multiprotein complexes [4,19]. The pervasiveness of the JmjC domain across animal phyla indicates that this evolutionarily conserved sequence has an important role in animal biology.