histone lysine demethylases

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Histone lysine Demethylases and their biological functions Sreejith, Neurogenetics laboratory, Hormone Research Center, School of Biological Sciences and Technology Chonnam National University The protein/DNA complex or rather chromatin is a package of genomic DNA and histone proteins in the eukaryotic cells. Nucleosome is the basic unit of the chromatin, which is composed of ~147 base pairs of DNA wrapped around an octamer of the four core histones (H2A, H2B, H3, and H4)(Fig). The core histones are tightly packed in globular regions with amino-terminal tails that extend from the globular region, making them accessible to histone modifying enzymes. Left, schematic of various levels of chromatin compaction, from extended nucleosome arrays to folding of secondary chromatin structures exemplified by the 30-nm chromatin fiber to poorly characterized higher-order structures. There are ten histone tails protruding from each nucleosome core. Right, detail of nucleosome surface showing histones H2A (yellow), H2B (light red), H3 (blue) and H4 (green). Residues comprising the charged pocket are shown in dark red. Nature Structural & Molecular Biology 14, 1056 - 1058 (2007)

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Page 1: Histone lysine Demethylases

Histone lysine Demethylases and their biological functions

Sreejith,Neurogenetics laboratory,

Hormone Research Center, School of Biological Sciences and TechnologyChonnam National University

The protein/DNA complex or rather chromatin is a package of genomic DNA and histone proteins in the eukaryotic cells. Nucleosome is the basic unit of the chromatin, which is composed of ~147 base pairs of DNA wrapped around an octamer of the four core histones (H2A, H2B, H3, and H4)(Fig). The core histones are tightly packed in globular regions with amino-terminal tails that extend from the globular region, making them accessible to histone modifying enzymes.

Left, schematic of various levels of chromatin compaction, from extended nucleosome arrays to folding of secondary chromatin structures exemplified by the 30-nm chromatin fiber to poorly characterized higher-order structures. There are ten histone tails protruding from each nucleosome core. Right, detail of nucleosome surface showing histones H2A (yellow), H2B (light red), H3 (blue) and H4 (green). Residues comprising the charged pocket are shown in dark red. Nature Structural & Molecular Biology 14, 1056 - 1058 (2007) 

The N-terminal tails of histones are subjected to several types of post-translational modifications, including acetylation, methylation, phosphorylation and ubiquitination. The combination of these modifications determines chromatin structure and transcriptional activation or repression of genes and key regulatory processes such as DNA replication and DNA repair.

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Chromatin modifications:

Most if not all of the histone modifications are dynamic in nature, providing reversible modes of regulation. Histone lysine methylation has been linked to DNA methylation, and is therefore

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strongly implicated in epigenetic regulation. Methylation takes place on the side chains of both lysine (K) and arginine (R) residues. A total of 6 major lysine residues (H3K4, H3K9, H3K27, H3K36, H3K79, and H4K20) have been shown to be mono-, di- and trimethylated.

Methylation of Histone Lysines

(Top) The enzymes that methylate and demethylate lysine (K) residues of histones H3 and H4 are shown. In higher eukaryotes, methylation of H4K20 (H4K20me1) is catalyzed exclusively by the methyltransferase PR-SET7 (the SUV4-20H1/2 enzymes are responsible for H4K20me2/3). H3K27 methylation (H3K27me, mediated by EZH1/2) and H4K20me1 (an autonomous mark independent from H4K20me2/3) are marks not found in unicellular organisms but which rather appeared with the emergence of multicellularity. Histone demethylases of the LSD1/BHC110 family are absent in the budding yeast Saccharomyces cerevisiae but are present in the fission yeast Schizosaccharomyces pombe. Certain proteins containing Jumonji (Jmj) domains, which are conserved from yeast to human, have histone demethylase activity. DOT1 is the only enzyme responsible for methylating H3K79, a methyl mark that is associated with maintaining open chromatin. H3K79me is also present in S. cerevisiae, and so we speculate that the epigenetic potential of H3K79me is different from that of H4K20me1 and H3K27me. (Bottom) The transmission of the epigenetic histone methyl marks H4K20me1 and H3K27me from parental to daughter chromosomes. (Bottom, left) The model proposes that H3K27me marks are transmitted during DNA replication. A Polycomb dimer binds to H3K27me on the parental chromatin and an unmethylated H3 tail from the newly synthesized chromatin. EZH2, the H3K27-specific histone lysine methyltransferase, is recruited and methylates H3K27 on the daughter strand. (Bottom, right) DNA is replicated in S phase, but H4K20me1 is not transmitted to newly synthesized chromosomes before mitosis. PR-SET7, the H4K20me1-specific histone lysine methyltransferase, is only expressed during mitosis. The enzyme directly (or indirectly through interaction with an unknown H4K20me1 binding protein) recognizes H4K20me1 on the parental chromosome and methylates the appropriate position on the daughter chromosome.

Patterns of specific lysine methyl modifications are achieved by a precise lysine methylation system, consisting of proteins that add, remove, and recognize the specific lysine methyl marks. The majority of these enzymes show significant substrate specificity. The maintenance of histone methylation balance requires the action of both methylases and demethylases. The first lysine specific histone demethylase LSD1 (also known as AOF2 and KDM1) was discovered in 2004. Subsequent to the discovery of LSD1, another family of more than 30 histone demethylases

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structurally different from LSD1 was described, all of which sharing a motif designated the Jumonji C (JmjC) domain and revealing a substrate specificity. The modulation of demethylase activity involves regulation at multiple levels, including gene expression, recruitment, coordination with other epigenetic marks, and post-translational modifications (PTMs)

LSD1 catalyzes the demethylation reaction of mono- and dimethylated histone H3 lysine 4. LSD1 is highly conserved in organisms ranging from Schizosaccharomyces pombe to human and consists of three major domains: an N-terminal SWIRM (Swi3p/Rsc8p/Moira) domain, a C-terminal AOL (amine oxidase-like) domain, and a central protruding Tower domain. The C-terminal catalytic domain reveals high sequence homology to polyamine oxidases, that belong to the FAD-dependent enzyme family.

Structure of human LSD1. (A) Domain structure. Gray, unstructured N-terminal region; yellow, SWIRM domain; red, SWIRM-oxidase connector; blue, oxidase domain; green, helical insertion.(B) Structure of LSD1 in complex with CoREST and a peptide substrate. LSD1 (blue) tightly associates with the CoREST C-terminal SANT domain(red). The histone H3 N-terminal peptide (residues 1-16; green) binds in the LSD1 amine oxidase domain in proximity to the flavin cofactor (yellow)

As mentioned above there are 2 main classes of histone lysine demethylases based on activity. The first class of enzyme is solely represented by LSD1/KDM1, whereas the remaining known demethylases fall into the Jumonji (JmjC)-domain-containing class. The proposed enzymatic mechanisms of these two distinct classes offer insights into their substrate specificity and necessary co-factors. Another category of enzymes, including peptidylarginine deiminase 4(PAD4), regulate histone arginine methylation by converting methylarginine to citrulline and releasing methylamine.

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Mechanism of Action of Histone Lysine Demthylases

LSD1-Mediated:

LSD1(lysine specific Demethylases 1) is a riboflavin-dependent H3K4-specific mono- and dimethyllysine demethylase. It catalyses the de-methylation of lysine residues by cleavage of the α-carbon bond of the substrate to generate an imine intermediate. The intermediate is subsequently hydrolyzed via a non-enzymatic process to produce a carbinolamine, which is unstable and degrades, releasing formaldehyde and amine. This reaction results in a hydride transfer with reduction of FAD to FADH2 that is re oxidized by molecular oxygen, producing hydrogen peroxide.

Demethylation of K4H3me2 by LSD1. First, the methylated Lys4 side chain of histone substrate is oxidized by the FAD prosthetic group with resultant reduction of oxygen to hydrogen peroxide. The resulting imine intermediates is hydrolyzed to generate the demethylated H3 tail and formaldehyde

Biochemical studies have demonstrated that LSD1 H3K4 demethylase activity for nucleosomal substrates is regulated by association with CoREST. CoREST contains an N-terminal histone deacetylase-interacting domain followed by two successive SANT (Swi3/Ada2/NCoR/transcription factor IIIB) domains, which are common features of chromatin-binding proteins. Modulation of LSD1 specificity can also be altered by association with other specific cofactors. LSD1 can change specificity from H3K4 to H3K9 when it is associated with the androgen receptor.

The androgen receptor shares a common modular structure with other nuclear receptors and is composed of several domains that mediate DNA binding, dimerization, ligand binding and

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transcriptional activity . Upon hormone binding, the cytoplasmatic androgen receptor dissociates from chaperones and translocates to the nucleus where it binds to androgen response elements(AREs) of target genes and regulates gene expression. During this step, LSD1 forms a chromatin-associated complex with the ligand-activated androgen receptor and is responsible for demethylation of the H3K9me1 and H3K9me2 at androgen receptor target genes such as prostate specific antigen (PSA) or kallikrein2.

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JmjC Mediated:

JmjC( JumonjiC/Jumonji histone demethylase-JHDM) class of histone demethylases operates via Fe(II) and 2-oxoglutarate-dependent dioxygenation. By analogy with other dioxygenases catalyzed by Fe(II)- and 2-oxoglutarate dependent dioxygenases, these enzymes likely proceed through a radical mechanism involving an iron-oxo intermediate.

An electron transferred from Fe(II) generates a superoxide radical that attacks C-2 of 2-oxoglutarate to form a covalent linkage between the Fe(IV) center and 2-oxoglutarate. Decarboxylation of the activated 2-oxoglutarate intermediate produces succinate and CO2 with the concomitant formation of an Fe(IV)-oxo intermediate. This Fe(IV)-oxo intermediate is then reduced upon abstraction of a hydrogen atom from the methyl group of the substrate, in the process generating a hydroxylated carbinolamine that spontaneously produces formaldehyde while regenerating the active Fe(II)center. It does not require a protonated nitrogen for activity like LSD1 and hence is capable of efficiently demethylating trimethylated lysine residues. The JmjC domain is conserved from bacteria

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to eukaryotes and belongs to the cupin superfamily of metalloenzymes. JmjC domain proteins are predicted to be hydroxylases and are chemically compatible with demethylation of methylated substrates. JHDM1 specifically demethylates H3K39me2.

The structure of the catalytic core of JHDM3 with and without α-ketoglutarate in the presence of Fe(II) reveals that the catalytic core consists of a 30-amino acid N-terminal JmjN domain comprising two short helices and a longer helix sandwiched between two β-strands.

JHDM2A, is involved in androgen receptor-dependent gene expression. The mechanism of action of JHDM2A differs from that of LSD1. JHDM2A, which demethylates H3K9me2, does not associate with chromatin as with LSD1, on androgen receptor-responsive genes in the absence of the receptor. JHDM2A interacts with the androgen receptor in a ligand-dependent manner and is recruited by the androgen receptor onto chromatin in response to hormone treatment during activation of the androgen receptor target genes PSA and NKX3.1.

The first JmjC domain demethylase described, was FBXL11 (synonyms: JHDM1a and KDM2A),which was shown to specifically demethylate mono- and dimethylated H3K36 in a Fe(II) and α-ketoglutarate(αKG)-dependent manner.

Jumonji proteins when segregated fall into specific clusters and each cluster has the specificity for demethylating a certain histone mark.

FBXL(KDM2) cluster:

Two proteins FBXL11 (synonyms: JHDM1a and KDM2A) and FBXL10 (synonyms: JHDM1b and KDM2B) constitute the FBXL cluster. Both proteins contain an F-box domain in addition to two leucine-rich repeat (LRR) domains (Fig. 2). FBXL11 was demonstrated to demethylate di- and monomethylated H3K36.

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JMJD1(KDM3) cluster:

JMJD1A (synonyms: TSGA, JDHM2A, and KDM3A) was originally isolated as a male germ-specific transcript. JMJD1A was later shown to be an H3K9me2/me1-specific demethylase. The protein features an LXXLL motif that is a signature involved in nuclear receptor interactions. The expression of JMJD1A is most prominent in testes, and has been implicated in demethylation of H3K9me2 of AR target genes. Human JMJD1B (synonyms: JHDM2B, 5qCNA and KDM3B) has also been identified as an H3K9me2/me1 demethylase.

JMJD2 (KDM4) cluster:

The JMJD2 cluster consists of four genes, JMJD2A (synonym: KDM4A), JMJD2B (synonym: KDM4B), JMJD2C(synonyms: GASC1 and KDM4C), and JMJD2D (synonym: KDM4D). They direct the expression of histone lysine demethylases capable of demethylating both the H3K9me3/me2 and H3K36me3/me2 marks.

JARID1 (KDM5) cluster:

The JARID1 subfamily of JmjC proteins encompasses four members: JARID1A, JARID1B, JARID1C, and JARID1D (also called KDM5A-D according to the novel nomenclature), which all can demethylate tri- and dimethylated H3K4. Tri- and dimethylation on histone H3 at Lys 4 (H3K4me3/me2) is often found at transcribed genes.

UTX/JMJD3(KDM) cluster:

This cluster consists of three proteins, UTX (synonym: KDM6A), UTY, and JMJD3 (synonym: KDM6B). UTX and JMJD3 are histone demethylases specific for H3K27me3/me2. UTX and UTY are highly

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homologous and characterized by the presence of 6 tetra tricopeptide repeat (TPR) domains in addition to the catalytic JmjC domain and a treble clef zinc-finger domain.

JARDI2 (Jumonji): The JARID2 protein also known as Jumonji (JMJ) is phylogeneticly closely related to the JARID1 family. As the JARID1 members, JARID2 features an Arid/Bright domain in addition to a JmjC and JmjN domain. The Jarid2 gene was originally identified in a genetrap screen for genes involved in mouse embryonic development.

PHD finger (PHF) cluster:

This cluster consists of three proteins that in addition to the JmjC domain contain a PHD finger domain: PHD finger protein 2 (PHF2), PHD finger protein 8 (PHF8), and KIAA1718.

HSPBAP1:Heat-shock 27 (Hsp27)-associated protein 1 (HSPBAP1, also denoted PASS1), is a member of the JmjC family, most closely related to JMJD5 and FIH (Fig. 2). The protein features an HXDX n H motif and could potentially be a histone demethylase.

Arginine demethylases

Deiminases might catalyze the reversal of arginine methylation. Members of the peptidyl arginine deiminase (PADI) family deiminate arginine residues by converting them into citrulline.

Enzymes that demethylate histonesThe enzymes identified that demethylate histones, subsequent subfamilies and specific substrates.

Enzymatic family Subfamily Enzyme(s) Specific activityPADI PADI4 H3R2, R8, R17, R26 H4R3Amine oxidase LSD1 H3K4me2, me1JmjC JHDM1 JHDM1A, JHDM1B H3K36me2, me1

PHF2/PHF8 PHF2, PHF8 UnknownJARID JARID1A/RBP2

JARID1B/PLU-1JARID1C/ SMCX1JARID1D/SMCY

H3K4me3, me2

JHMD3/JMJD2 JMJD2/JHDM3AJMJD2BJMJD2C/GASC1JMJD2D

H3K9me3, me2H3K36me3, me2

UTX/UTY JMJD3 UTX

H3K27me3, me2

JHDM2 JHDM2AJHDM2BJHDM2C

H3K9me3, me2

JmjC only MINA53JMJD4JMJD5

Unknown

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Regulation of Histone Lysine Demethylases:

Once present in the cell the activity of a demethylase is controlled in a modular and step-wise fashion, integrating input from protein–protein interactions with DNA-binding factors and other chromatin modifying enzymes, recognition of chromatin state by additional non-enzymatic ‘reader’ domains present in the demethylases and/or their associated proteins, as well as possible associations with non-coding RNAs. The demethylase expression pattern in development has been reported in mammal, fly and worm. There is some restricted pattern of embryonic and adult expression.

Biochemical studies have identified the presence of several demethylases in protein complexes with known DNA-binding transcription factors. The H3K4me3 demethylase KDM5C/JARID1C has been shown to be associated with the DNA-sequence-specific REST repressive complex, responsible for repression of neuronal genes in non-neuronal tissues. A number of DNA-binding transcription factors have been implicated in recruiting the various histone demethylases to specific genomic locations.

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Transcription factors, in addition to the recruitment role can modulate the activities of demethylases and alter their function in transcription regulation. Transcription factor binding may also alter the substrate specificity of demethylases. KDM1/LSD1 was shown to cooperate with the H3K9me3 demethylase KDM4C/JMJD2C to activate AR-responsive target genes

It is speculated that recruitment plays a crucial role in demethylase biology and that local chromatin environments, such as specific histone modifications recognized by specific protein modules built into the demethylases or associated proteins, offer additional selectivity for demethylase recruitment.

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Possible epigenetic mechanisms involved in H3K4me and H3K27me regulation (a) KDM1/LSD1-mediated H3K4me2 demethylation. A stepwise working model for KDM1/LSD1 complex is illustrated. The whole process involves HDAC-mediated deacetylation, CoREST binding, KDM1/ LSD1-mediated H3K4 demethylation, and BHC80 binding (H3K4me0). (b) A proposed model for resolving bivalent domain to monovalent domain. In the pluripotency stage, the ‘bivalent domain’ is established by MLL and PRC complexes, and the recruitments of H3K27 and H3K4 demethylases are absent. During differentiation, the methylase complexes are selectively kept, and demethylases are differentially recruited, resulting in a H3K4me3-only or H3K27me3-only domain.

The first 36 amino acids of the histone H3 tail and lysine residue 79 are shown. Lysine residues that undergo methylation are highlighted in green to indicate active transcription, and red to indicate transcriptional repression. The histone methyltransferases for various lysine residues on histones are shown at the top and the corresponding demethylases are shown at the bottom. The mammalian counterparts are indicated for most of the known enzymes. AR, androgen receptor; ASH1, ASH1 (absent, small or homeotic)-like (Drosophila); DOT1, disruptor of telomeric silencing 1; EZH2, Enhancer of zeste homologue 2; FBXL10, F-box and leucine-rich repeat protein 10; G9a, also known as EHMT2 (euchromatic histone-lysine N-methyltransferase 2); HYPB, huntingtin-interacting protein B; JHDM, JmjC-domain-containing histone demethylase; JMJD, Jumonji-domain-containing protein; LSD1, lysine-specific histone demethylase 1; MLL, myeloid/lymphoid or mixed-lineage leukemia-associated protein; NSD1, nuclear receptor-binding SET-domain protein 1; PLU-1, also known as JARID1B (Jumonji, AT-rich interactive domain 1B); RIZ1, retinoblastoma protein-interacting zinc-finger protein; RPB2, also known as JARID1A; SET1, SET-domain-containing histone methyltransferase; SMCX, also known as JARID1C; SMCY, also known as JARID1D; SMYD2, SET and MYND domain containing 2; SUV39H, suppressor of variegation 3-9 homologue; UTX, ubiquitously transcribed tetratricopeptide repeat, X chromosome.

FUNCTIONAL Aspects:

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The patterns and levels of histone methylation have been linked to many important biological processes such as stem cell maintenance and differentiation, X inactivation, and DNA damage response. Mutations or translocations of histone methyltransferases have been directly linked to prostate, breast, and hematopoietic cancers, emphasizing the importance of histone methylation balance in vivo.

LSD1 controls the tumor suppressor activity of p53 by demethylating a specific p53 lysine (Lys370) which is required for efficient binding to the transcriptional co-activator p53-binding protein-1. Through this interaction, LSD1 blocks p53 proapoptotic activity. A DNA methyltransferase was also indentified as a non-histone substrate for LSD1. Methylation of DNMT1 leads to protein degradation. LSD1 can directly demethylate and stabilize DNMT1 maintaining global DNA methylation. Thus, LSD1 coordinates not only histone methylation but also DNA methylation to regulate chromatin structure and gene activity. LSD1 appears to be pivotal in development and differentiation. LSD1 also play conserved roles in meiosis and germ cell development. The dual role of LSD1 in gene repression and activation is demonstrated by the fine regulation of growth hormone expression during pituitary development. In addition to its transcriptional regulation of individual genes, LSD1 plays an important role in inter-chromosomal interaction and nuclear rearrangement.

LSD1 is associated with complexes that function as both transcriptional repressors and activators. It demethylates H3K4me2/me1 when associated with the Co-REST complex at neuronal genes, or, H3K9me2/me1 when associated with the androgen receptor (AR). LSD1 is also thought to function in the organization of higher-order chromatin structure by two different mechanisms. The LSD1 homologs in S. pombe (spLsd1/2 also known as SWIRM1/2) exhibit H3K9me demethylase activity and are associated with heterochromatin boundaries and euchromatic promoters . Loss of spLsd1 induces heterochromatic propagation beyond normal regions. In addition a decrease in gene transcription is observed at adjacent sites, which correlates with an increase in H3K9me. The Drosophila homolog Su(var)3-3 demethylates H3K4me but is also important for heterochromatin formation (Rudolph et al., 2007). Demethylation of H3K4me1 and me2 is needed for subsequent H3K9me and heterochromatin formation.

Increasing evidence shows that histone H3K4 methylation is a specific epigenetic mark associated with the promoters of actively transcribed genes. It serves as a docking site for various cofactors that promote chromatin remodeling to increase the accessibility of transcription factor binding sites on DNA, permitting increased transcription.

Lysine specific demethylase 1, (LSD1) is responsible for removing the repressive histone codes during C2C12 mouse myoblast differentiation. The regulatory mechanism of myogenesis involves histone demethylase.

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FBXL10 is a candidate tumor suppressor gene. Retroviral insertional mutagenesis within the FBXL10 gene has been shown to cause lymphoma in BLM (Bloom syndrome RecQ protein-like-3 DNA helicase)deficient mice. Second, inhibition of FBXL10 expression increases cell proliferation. FBXL10 expression is significantly decreased in various primary brain tumors, including glioblastoma multiforme. These proteins regulate transcription through the combined action of demethylation and ubiquitylation of transcription factors or other proteins associated with transcription.

JMJD1A fulfills the essential roles for spermiogenesis, and its disruption causes male infertility phenotypes reminiscent of human syndromes as azoospermia and globospermia, advancing JMJD1A as a candidate gene for these infertility conditions. JMJD1A was found to associate with the cardiac and smooth muscle cell (SMC)-specific transcription factor myocardin and the related proteins MRTF-A and MRTF-B. JMJD1A is involved in regulating SMC differentiation.

The enzymatic activity of JMJD2 proteins toward demethylation of the repressive marks H3K9me3/me2 indicates that these proteins work as transcriptional coactivators. JMJD2 proteins are oncogenes, which contribute to tumor formation by (1) inducing genomic instability, (2) suppressing of cellular senescence, or (3) activating transcription. The involvement of the JMJD2 proteins in tumorigenesis has been supported further by a recent report demonstrating the functional interaction between JMJD2C and the AR in prostate carcinomas. The JMJD2 proteins have also been proposed to work as transcriptional repressors: JMJD2A has been shown previously to be associated with the transcriptional repressor complex, N-CoR. JARID1 proteins function as

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transcriptional repressors through the demethylation of H3K4me3/me2, and through the recruitment of other repressive chromatin modifiers.

Role in senescence:Cellular senescence constitutes a barrier against excessive cell proliferation, and is a specific form for irreversible growth arrest that can be induced by a number of different stress inducers, including activation of oncogenes and DNA damage, as well as telomere erosion. Trimethylation of H3K9 plays a key role in the establishment of SAHFs and induction of the senescent state. Demethylases removing the repressive H3K9me3 marks may act to increase genomic instability, dissolve SAHFs, and prevent or override senescence induction, and may thus potentially providecancer cells with the possibility to evade the important tumor suppressor mechanism.

Another demethylase family, which potentially could be involved in the senescence process, is the UTX/JMJD3 family of H3K27 demethylases. The polycomb-repressive complexes PRC2 and PRC1, which catalyze methylation of H3K27 and are involved in chromatin compaction, respectively, are over-expressed or amplified in cancer.

Studies in multiple model systems have shown that H3K4me and H3K9me, in particular, are present in chromatin in defined patterns during meiosis, and that the perturbation of the enzymes that regulate these modifications leads to defects in many essential meiotic steps. Collectively, these studies suggest that the dynamic regulation of histone methylation by both KMTs and KDMs might be one way to monitor meiotic progression. Studies of several demethylases suggest that they help to modulate the progression of pluripotent progenitor cell types into

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differentiated cell lineages during development. LSD1/KDM1 has a particularly interesting expression pattern in early mammalian development.

In mammals, two large biochemical complexes, analogous to the Trx and PcG complexes that exist in flies, might act to coordinately regulate H3K4me3 and H3K27me3 so that only one modification is dominant on the target gene in differentiated cells. These complexes therefore contain opposing enzymatic activities that control and coordinate the balance of histone methylation at H3K4 and K3K27.

Demethylases in neural differentiation and disease: A role for H3K27me3 demethylation in mammalian neuronal development has been identified through studies of the co-repressor, silencing mediator for retinoid and thyroid hormone receptor (SMRT; also known as NCOR2), which is crucial for mouse forebrain development and for the maintenance of pluripotency.

Drosophila Little imaginal discs (Lid) is a recently described member of the JmjC domain class of histone demethylases that specifically targets trimethylated histone H3 lysine 4 (H3K4me3). Lid's JmjC domain-encoded demethylase activity is dispensable for normal development, Loss of Lid's demethylase activity is compensated for by dKDM2. The Essential functions of Lid are encoded by its JmjN, C5HC2 and C-terminal PHD zinc finger motifs also the N- and C-terminal PHD fingers of Lid bind specific methylated forms of histone tails and Lid's C-terminal H3K4me2/3 binding PHD finger is required for it to function in dMyc-mediated cell growth.

Connections between histone demethylases and human disease

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