Trends in Cell Biology
ReviewHistone demethylases in development and disease
Introduction
Eukaryotic DNA is packed into chromatin whose basic repeating unit is the nucleosome. The nucleosome contains 145-147 base pairs of DNA wrapped nearly twice around an octamer of the core histones, H2A, H2B, H3 and H4. In addition, the linker histone, H1, helps further compact the nucleosomal DNA into higher-order structures. Histones, especially their flexible tails extending from the nucleosomal core, are subjected to numerous post-translational modifications, which include methylation, acetylation, phosphorylation, ubiquitylation and SUMOylation. Histone methylation occurs on lysines and arginines. Adding complexity, residues can exist in different methylated forms with lysines (K), being either mono- (me1), di- (me2) or tri-methylated (me3), and arginines (R) being monomethylated or symmetrically or asymmetrically dimethylated. In general, trimethylation of H3K4, H3K36 and H3K79 are found in euchromatic regions with transcriptional activity, whereas H3K9me3/me2, H4K20me3 and H3K27me3 are associated with transcriptionally silenced chromatin. Histone modifications are believed to be important for coordinating both transient changes in gene transcription, as well as for maintaining differential patterns of gene expression during organismal development. Chromatin architecture also impinges on genomic stability, being linked to processes such as DNA repair and chromosome segregation.
Histone modifications have been suggested to be part of a ‘code’ that is read by proteins via specific binding domains, and in this way translated into a functional signal [1]. Thus histone modifications can influence chromatin condensation, and poise genes for either transcriptional activation or repression, depending on how the modification is read and translated in a specific context. While individual histone marks have been correlated with either active or silenced transcriptional states, many modifications have several, seemingly opposing roles, and the combination of marks, as well as their genomic context, appear to be essential for the biological output (reviewed in 2, 3, 4).
Our current knowledge regarding histone methylation stems in large part from the study of histone methyltransferases. Several of these enzymes are essential for development, and deregulated expression has been linked to human disorders such as cancer (reviewed in [5]). The more recent discovery of histone demethylases (Box 1) made a significant impact on the perception of histone methylation as permanent, inheritable marks supporting more dynamic roles in gene regulation.
Two classes of histone demethylases have thus far been identified. The proteins of the KDM1 (Lysine (K) Demethylase 1) family are FAD-dependent amine oxidases, which can act only on mono- and dimethylated lysines (Figure 1, Figure 2, Table 1). The Jumonji C (JmjC) domain is a signature motif for the other class of demethylases, which are Fe(II) and 2-oxoglutarate-dependent enzymes. Based on sequence homology in the JmjC domain and the overall architecture of associated motifs, JmjC domain-containing proteins have been classified into different groups, several of which have been found to possess histone demethylase activity (Figure 1, Figure 2, Table 1).
Here we review the current knowledge regarding histone demethylases with a particular focus on their potential roles in development and disease.
Section snippets
The KDM1 family
The first protein demonstrated to possess histone demethylase activity was mammalian KDM1A/AOF2 (amine oxidase (flavin containing) domain 2)/LSD1 (lysine-specific demethylase 1). In an elegant study, Shi and co-workers found that KDM1A could demethylate H3K4me2/me1 [7]. Subsequent studies have shown histone demethylase activity for the closely related KDM1B/AOF1/LSD2, as well as for orthologues in other species 8, 9, 10, 11.
Highlighting the importance of KDM1A for normal development, targeted
The KDM2 cluster
The first JmjC domain-containing protein shown to be a histone demethylase was KDM2A/JHDM1A (JmjC domain-containing histone demethylation protein 1A)/FBXL11 (F-box and leucine-rich repeat protein 11) [29]. Mammalian KDM2A and KDM2B/JHDM1B/FBXL10, as well as the homologues in Drosophila and S. cerevisiae, have been demonstrated to catalyze H3K36me2/me1 demethylation 29, 30, 31. In addition, mammalian KDM2B has been suggested to act as an H3K4me3 demethylase 32, 33, but discrepancy exists about
The KDM3 cluster
KDM3A/JHDM2A/JMJD1A (jumonji domain-containing 1a)/TSGA (testis-specific gene A) is a histone demethylase specific for H3K9me2/me1 [43]. Two KDM3A homologues exist in mammalian cells - KDM3B/JHDM2B/JMJD1B and JMJD1C/JHDM2C/TRIP8 (thyroid receptor interacting protein 8) - but demethylase activities of these proteins have not been reported so far.
Studies of genetrap and knockout mice have demonstrated important roles for KDM3A in germ cell development and metabolism 44, 45, 46, 47. KDM3A is
The KDM4 cluster
The KDM4 proteins were the first published demethylases that showed activity towards trimethylated lysines. There are four members of the KDM4 cluster in mammalian cells - KDM4A/JHDM3A/JMJD2A, KDM4B/JHDM3B/JMJD2B, KDM4C/JHDM3C/JMJD2C/GASC1 (gene amplified in squamous cell carcinoma 1) and KDM4D/JHDM3D/JMJD2D. The KDM4 proteins catalyze the demethylation of H3K9me3/me2 and/or H3K36me3/me2, with the substrate specificity varying between family members 50, 51, 52, 53, 54. Moreover, the KDM4
The KDM5 cluster
The KDM5 proteins catalyze the demethylation of H3K4me3/me2 62, 63, 64, 65, 66, 67. In mammalian cells, the KDM5 family is constituted by KDM5A/JARID1A (Jumonji, AT-rich interactive domain 1A)/RBP2 (retinoblastoma-binding protein 2), KDM5B/JARID1B/PLU-1, KDM5C/JARID1C/SMCX (selected mouse cDNA on the X) and KDM5D/JARID1D/SMCY.
Important developmental functions have been demonstrated for the KDM5 proteins in C. elegans and Drosophila. In C. elegans, deletion of the JmjC domain of RBR-2
The KDM6 cluster
The KDM6 cluster in mammalian cells consists of KDM6A/UTX (ubiquitously transcribed X chromosome tetraticopeptide repeat protein), UTY and KDM6B/JMJD3. Whereas KDM6A and KDM6B are histone demethylases specific for H3K27me3/me2, no activity has so far been reported for UTY 85, 86, 87, 88.
The importance of H3K27 demethylases in normal development is underscored by studies in C. elegans and D. rerio. In C. elegans, mutation of one of the three KDM6B homologues disrupts gonadal development [85],
The PHF cluster
Recently, histone demethylase activity has been reported for the PHF (plant homeodomain finger protein) cluster of the JmjC family of proteins. Mammalian PHF8 possesses H3K9me2/me1 activity 99, 100, 101, 102, whereas JHDM1D/KIAA1718 targets both H3K9me2/me1 and H3K27me2/me1 99, 103, 104. PHF2 has been suggested to demethylate H3K9me1, but this has yet to be confirmed by in vitro studies [105].
Intriguingly, mutations in the human PHF8 gene might, like KDM5C mutations, be relevant for the
JMJD6
JMJD6/PSR/PTDSR (phosphatidylserine receptor) is the first demethylase described to target arginine residues and was reported to demethylate H3R2me2 and H4R3me2 [109]. However this activity has been questioned recently, and it has been demonstrated that JMJD6 has strong lysyl hydroxylation activity towards the splicing factor U2AF2 (U2 small nuclear ribonucleoprotein auxiliary factor) [110]. Originally, JMJD6 was identified as the phosphatidylserine receptor responsible for recognizing
Perspectives and concluding remarks
Since the discovery of the first bona fide histone demethylase, several proteins have been demonstrated to possess demethylase activity, and more demethylases will most likely be identified in the coming years. With the identification of histone demethylases, it became clear that histone methylation patterns are the result of equilibria between opposing activities. Tremendous progress has been made towards unravelling the cellular functions of histone demethylases, but many important questions
Acknowledgements
We thank Jesper Christensen and Paul Cloos for help with illustrations and members of the Helin lab for critical comments on the manuscript. MTP was supported by fellowships from P. Carl Petersen's Foundation and the Danish Cancer Society. The work in the Helin lab is supported by grants from the Danish National Research Foundation, the Danish Cancer Society, The Lundbeck Foundation, the Novo Nordisk Foundation, the Danish Medical Research Council, and the Excellence Program of the University
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