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evolution
KDM4A belongs to the KDM4 family
evolution
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Rph1 is a histone demethylase containing a Jumonji C (JmjC) domain and belongs to the C2H2 zinc-finger protein family
evolution
the enzyme belongs to the Jmjd2 family of H3K9/H3K36 histone demethylases
evolution
the enzyme belongs to the KDM2-8 family, KDM4 (also known as JMJD2) subfamily, which divided into five isoforms A-E
evolution
enzyme CG15835 shows higher identity to mammalian JMJD2D (40%) than to any of the other mammalian JMJD2 isoforms (22%)
evolution
enzyme CG33182 shows higher identity to mammalian JMJD2D (40%) than to any of the other mammalian JMJD2 isoforms (22%)
evolution
JMJD2A is a JmjC histone demethylase (HDM)
evolution
the Drosophila melanogaster HDM gene Dmel\Kdm4A is a homologue of the human JMJD2 family. Dmel\JHMD1, Dmel\JHMD2, and Dmel\Kdm4A are each highly conserved with their human homologue counterparts
evolution
the enzyme belongs to the KDM4/JmjC demethylase histone demethylase family. The selectivity of KDM4 enzymes is determined by multiple interactions within the catalytic domain but outside the active site. All KDM4 subfamily members have highly conserved residues lining the methylammonium-binding pocket. The exceptions are Ser288A/Ser-289B/Ser290C and Thr289A/Thr290B/Thr291C in KDM4A, B, and C, which are substituted by Ala287D/Ala289E/Ala286F and Ile288D/Ile290E/Ile287F in KDM4D-F, respectively. Evolutionary analysis of the KDM4 demethylase subfamily
evolution
the enzyme belongs to the KDM4/JmjC demethylase histone demethylase family. The selectivity of KDM4 enzymes is determined by multiple interactions within the catalytic domain but outside the active site. Evolutionary analysis of the KDM4 demethylase subfamily
evolution
the enzyme encoded by gene AN1060 (designated as kdmA) is a member of the mammalian KDM4 family of proteins (also known as JHDM3/JMJD2 in mammals)
evolution
the human KDM4 family consists of four members, KDM4A-D (also known as JMJD2A-D). These enzymes specifically catalyze the demethylation of H3K9me3/me2, H3K36me2/me3 and H1.4K26me2/me3 in a Fe2+ and 2-oxoglutarate-dependent manner. Besides the catalytic JmjC domain, KDM4 demethylases contain the JmjN domain, which is also required for the demethylase activity. In addition, all KDM4 members, except the shortest KDM4D protein, contain two Plant homeodomain (PHD) and two Tudor domains. Gene KDM4D is Y chromosome-encoded and a truncated enzyme variant compared to KDM4A-C
evolution
the human KDM4 family consists of four members, KDM4A-D (also known as JMJD2A-D). These enzymes specifically catalyze the demethylation of H3K9me3/me2, H3K36me2/me3 and H1.4K26me2/me3 in a Fe2+ and 2-oxoglutarate-dependent manner. Besides the catalytic JmjC domain, KDM4 demethylases contain the JmjN domain, which is also required for the demethylase activity. In addition, all KDM4 members, except the shortest KDM4D protein, contain two Plant homeodomain (PHD) and two Tudor domains. PHD and Tudor domains are not required for KDM4 enzymatic activity. Gene KDM4D is Y chromosome-encoded and a truncated enzyme variant compared to KDM4A-C
evolution
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Rph1 is a histone demethylase containing a Jumonji C (JmjC) domain and belongs to the C2H2 zinc-finger protein family
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evolution
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the enzyme belongs to the Jmjd2 family of H3K9/H3K36 histone demethylases
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malfunction
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enzyme mutants show 99 misregulated genes in first instar larvae. dKDM4A overexpression results in a global decrease in H3K36me3 levels and male lethality, which might be caused by impaired dosage compensation
malfunction
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histone H3K36A mutant shows increased UV sensitivity. Deletion of rph1 leads to approximately 2fold enhancement of PHR1 under normal conditions. Overexpression of Rph1 reduces the expression of PHR1 and increased UV sensitivity. The catalytically deficient mutant H235A of Rph1 diminishes the repressive transcriptional effect on PHR1 expression, which indicates that histone demethylase activity contributes to transcriptional repression
malfunction
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more than 75% of Rph1-regulated genes show increased expression in the rph1-deletion mutant
malfunction
changes in RENT component recruitment at NTS regions due to loss of H3 methylases or demethylases
malfunction
dysregulated expression of KDM4A-D family promotes chromosomal instabilities
malfunction
disruption of Dmel\Kdm4A results in a reduction of the male life span and a male-specific wing extension/twitching phenotype that occurs in response to other males and is reminiscent of an inter-male courtship phenotype involving the courtship song, phenotypes overview. Certain genes associated with each of these phenotypes are significantly downregulated in response to Dmel\Kdm4A loss, most notably the longevity associated Hsp22 gene and the male sex-determination fruitless gene
malfunction
dysregulated expression of KDM4A-D family promotes chromosomal instabilities. Dysregulation of KDM4C expression promotes mitotic chromosome missegregation. KDM4B-C members are overexpressed in several types of human cancer and its depletion impairs cancer cell proliferation
malfunction
dysregulated expression of KDM4A-D family promotes chromosomal instabilities. KDM4B-C members are overexpressed in several types of human cancer and its depletion impairs cancer cell proliferation
malfunction
KDM4A/JMJD2A overexpression leads to localized copy gain of 1q12, 1q21, and Xq13.1 without global chromosome instability, KDM4A-amplified tumors have increased copy gains for these same regions. 1q12h copy gain occurs within a single cell cycle, requires S phase, and is not stable but is regenerated each cell division. Sites with increased copy number are rereplicated and have increased KDM4A, MCM, and DNA polymerase occupancy. Suv39h1/KMT1A or HP1gamma overexpression suppresses the copy gain, whereas H3K9/K36 methylation interference promotes gain. Overexpression of a chromatin modifier results in site-specific copy gains
malfunction
knocking down JMJD2B expression by siRNA in gastric and other cancer cells inhibits cell proliferation and/or induces apoptosis and elevates the expression of p53 and p21CIP1 proteins, mechanism of JMJD2B inhibition, overview. The enhanced p53 expression results from activation of the DNA damage response pathway
malfunction
lack of either Jmjd2a or Jmjd2b is compatible with embryonic stem cell self-renewal and embryonic development. Only specific genomic elements are affected upon loss of Jmjd2 function
malfunction
lack of either Jmjd2a or Jmjd2b is compatible with embryonic stem cell self-renewal and embryonic development. While individual Jmjd2 family members are dispensable for embryonic stem cell maintenance and embryogenesis, combined deficiency for specifically Jmjd2a and Jmjd2c leads to early embryonic lethality and impaired embryonic stem cell (ESC) self-renewal, with spontaneous differentiation towards primitive endoderm under permissive culture conditions, phenotype, overview. Only specific genomic elements are affected upon loss of Jmjd2 function. Loss of Jmjd2a and Jmjd2c has a drastic effect on ESC proliferation
malfunction
loss of JmjD2A function causes dramatic downregulation of neural crest specifier genes analyzed by multiplex NanoString and in situ hybridization. Cells overexpressing JmjD2A completely lack either H3K9me3 or H3K36me3 marks. Overexpression of JmjD2A in chicken fibroblasts specifically depletes H3K9me3 and H3K36me3. JmjD2A loss of function depletes Sox10 expression and expression of neural crest specifier genes Sox9, FoxD3, and Snail2, but not dorsal neural tube markers. JmjD2A knockdown inhibits demethylation of H3K9me3 on the Sox10 promoter
malfunction
mutations of the residues comprising the methylammonium-binding pocket abrogate demethylation by JMJD2A, with the exception of an S288A substitution, which augments activity, particularly toward H3K9me2
malfunction
overexpression of CG15835 results in spreading of HP1 into euchromatin and a strong decrease on the levels of H3K9me3 and H3K36me3, while the levels of H3K4me3 and H3K27me3 are not significantly altered. Demethylase activity of dJMJD2(1)/CG15835 depends on the JmjC domain, as it is abolished by mutations that affect its catalytic activity. The single-point mutation H195A, mutating one of the Fe2+ binding residues, abolishes demethylase activity of dJMJD2(1)/CG15835
malfunction
overexpression of the histone lysine demethylase KDM4A is related to the pathology of several human cancers
malfunction
Pim1 knockdown and P21(WAF1/Cip1) overexpression fully abrogates the oncogenic function of JMJD2A. A 39KD JMJD2A transcript, JMJD2ADELTA, is significantly increased in JMJD2A or miR372 overexpressing Hep3B cell line
malfunction
the kdmA mutant shows a significant increase in H3K36me3 during primary metabolism at the aflR and ipnA locus and some slightly higher levels at the aptA genes, the mutant has reduced levels of sterigmatocystin compared to wild-type. Manipulation of kdmA expression reveals genetic and environmental interactions including lethality under light. Deletion of kdmA causes light lethality and sensitivity to oxidative stress during vegetative growth to chronic oxidative stress
malfunction
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histone H3K36A mutant shows increased UV sensitivity. Deletion of rph1 leads to approximately 2fold enhancement of PHR1 under normal conditions. Overexpression of Rph1 reduces the expression of PHR1 and increased UV sensitivity. The catalytically deficient mutant H235A of Rph1 diminishes the repressive transcriptional effect on PHR1 expression, which indicates that histone demethylase activity contributes to transcriptional repression
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malfunction
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more than 75% of Rph1-regulated genes show increased expression in the rph1-deletion mutant
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malfunction
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the kdmA mutant shows a significant increase in H3K36me3 during primary metabolism at the aflR and ipnA locus and some slightly higher levels at the aptA genes, the mutant has reduced levels of sterigmatocystin compared to wild-type. Manipulation of kdmA expression reveals genetic and environmental interactions including lethality under light. Deletion of kdmA causes light lethality and sensitivity to oxidative stress during vegetative growth to chronic oxidative stress
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malfunction
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the kdmA mutant shows a significant increase in H3K36me3 during primary metabolism at the aflR and ipnA locus and some slightly higher levels at the aptA genes, the mutant has reduced levels of sterigmatocystin compared to wild-type. Manipulation of kdmA expression reveals genetic and environmental interactions including lethality under light. Deletion of kdmA causes light lethality and sensitivity to oxidative stress during vegetative growth to chronic oxidative stress
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malfunction
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the kdmA mutant shows a significant increase in H3K36me3 during primary metabolism at the aflR and ipnA locus and some slightly higher levels at the aptA genes, the mutant has reduced levels of sterigmatocystin compared to wild-type. Manipulation of kdmA expression reveals genetic and environmental interactions including lethality under light. Deletion of kdmA causes light lethality and sensitivity to oxidative stress during vegetative growth to chronic oxidative stress
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malfunction
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lack of either Jmjd2a or Jmjd2b is compatible with embryonic stem cell self-renewal and embryonic development. While individual Jmjd2 family members are dispensable for embryonic stem cell maintenance and embryogenesis, combined deficiency for specifically Jmjd2a and Jmjd2c leads to early embryonic lethality and impaired embryonic stem cell (ESC) self-renewal, with spontaneous differentiation towards primitive endoderm under permissive culture conditions, phenotype, overview. Only specific genomic elements are affected upon loss of Jmjd2 function. Loss of Jmjd2a and Jmjd2c has a drastic effect on ESC proliferation
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malfunction
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lack of either Jmjd2a or Jmjd2b is compatible with embryonic stem cell self-renewal and embryonic development. Only specific genomic elements are affected upon loss of Jmjd2 function
-
malfunction
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the kdmA mutant shows a significant increase in H3K36me3 during primary metabolism at the aflR and ipnA locus and some slightly higher levels at the aptA genes, the mutant has reduced levels of sterigmatocystin compared to wild-type. Manipulation of kdmA expression reveals genetic and environmental interactions including lethality under light. Deletion of kdmA causes light lethality and sensitivity to oxidative stress during vegetative growth to chronic oxidative stress
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malfunction
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the kdmA mutant shows a significant increase in H3K36me3 during primary metabolism at the aflR and ipnA locus and some slightly higher levels at the aptA genes, the mutant has reduced levels of sterigmatocystin compared to wild-type. Manipulation of kdmA expression reveals genetic and environmental interactions including lethality under light. Deletion of kdmA causes light lethality and sensitivity to oxidative stress during vegetative growth to chronic oxidative stress
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metabolism
different roles of histone H3 methylases in regulating Net1/Sir2 recruitment to rDNA regions and the resultant rDNA silencing. In particular, both H3K4 and H3K79 methylation by Set1 and Dot1 positively regulate rDNA silencing, whereas H3K36 methylation by Set2 has the opposite effect
metabolism
exposure to Co2+ increases gene repression markers (H3K9me3, H3K27me3, H3K36me3, H3K9me2, uH2A and lack of AcH4), as well as gene activation markers (H3K4me3 and uH2B) in both A549 and Beas-2B cells. Cobalt ions increase H3K9me3 and H3K36me3 by inhibiting histone demethylation process in vivo
metabolism
KDM4A possesses the potential to act as an oxygen sensor in the context of epigenetic regulation
metabolism
many JmjC HDMs appear to function in the context of large multimeric complexes that govern their localization, transcriptional functions, and potentially their substrate specificity. In the case of certain JmjC enzymes, these complexes appear to be critical in conferring specificity for nucleosomal substrates
metabolism
the FBXO22-containing SCF E3 ubiquitin ligase complex controls the activity of KDM4A by targeting it for proteasomal turnover in a ubiquitin K48-dependent manner. FBXO22 functions as a receptor for KDM4A by recognizing its catalytic JmjN/JmjC domains via its intracellular signal transduction domain. Modulation of FBXO22 levels leads to increased or decreased levels of KDM4A, respectively. Changes in KDM4A abundance correlate with alterations in histone H3 lysine 9 and 36 methylation levels, and transcription of a KDM4A target gene, ASCL2
physiological function
c-Rph1, the catalytic core of Rph1, is responsible for the demethylase activity, which is essential for the transcription elongation of some actively transcribed genes
physiological function
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dKDM4A demethylase activity regulates eu- and heterochromatic genes
physiological function
histone demethylase JMJD2B regulates chromatin structure or gene expression by removing methyl residues from trimethylated lysine 9 on histone H3 and is required for tumor cell proliferation and survival in vitro and in vivo, and is overexpressed in gastric cancer
physiological function
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histone H3K36 demethylase Rph1/KDM4 regulates the expression of the photoreactivation gene PHR1, the demethylation at H3K36 is linked to UV sensitivity. Overexpression of Rph1 and H3K36A mutant reduced histone acetylation at the URS, which implies a crosstalk between histone demethylation and acetylation at the PHR1 promoter. Rph1 is a repressor of the DNA repair gene PHR1. Rph1 is dissociated from the PHR1 promoter in response to DNA damage. Rad53 regulates the expression of PHR1 and dissociation of Rph1 in response to DNA damage. Activated Rad53 complex phosphorylates Rph1 and S652A-mutated Rph1 impairs the dissociation in response to DNA damage
physiological function
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identification of dKDM4A-regulated genes, overview. Appropriate expression levels for some dKDM4A-regulated genes rely on the demethylase activity of dKDM4A, whereas others do not. Highly expressed, many demethylase-dependent and independent genes are devoid of H3K36me3 in wild-type as well as in dKDM4A mutant larvae. Some of the most strongly affected genes in dKDM4A mutant animals are not regulated by H3K36 methylation
physiological function
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Rph1 might be a regulatory node connecting different signaling pathways responding to environmental stresses. Rph1 is mainly a transcriptional repressor. Rph1-regulated genes respond to DNA damage and environmental stress. Microarray analysis, overview
physiological function
changes in histone H3 lysine methylation levels distinctly regulate rDNA silencing by recruiting different silencing proteins to rDNA, thereby contributing to rDNA silencing and nucleolar organization in yeast. The Rph1/Kdm4 demethylase is a JHDM3/JMJD2 orthologue and has in vivo demethylase activity toward H3K36me3/2. Enzyme Rph1 positively affects transcription
physiological function
Rph1 and Gis1 are reported to regulate the expression of PHR1, a photolyase gene required for the light-dependent repair of pyrimidine dimers. Both demethylases contain two zinc fingers and are damage responsive repressors of PHR1. Rph1 positively affects transcription
physiological function
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anticancer agent nutlin kills MDM2-amplified cancer cells by altering histone methylation in an MDM2 proto-oncogene-dependent manner. MDM2 amplification increases histone methylation in nutlin-treated cells by causing depletion of histone demethylase JMJD2B. JMJD2B knockdown or inhibition increases H3K9/K36me3 levels, decreases ATG gene expression and autophagy, and sensitizes MDM2-nonamplified cells to apoptosis
physiological function
H3K36me3 acts as a barrier that prevents spreading of HP1 into euchromatin. Both H3K36 and H3K4 methylation associate to actively transcribed genes, suggesting that gene activity is a main determinant to delimit hetero- and euchromatic territories
physiological function
H3K36me3 acts as a barrier that prevents spreading of HP1 into euchromatin. Both H3K36 and H3K4 methylation associate to actively transcribed genes, suggesting that gene activity is a main determinant to delimit hetero- and euchromatic territories. dJMJD2(1)/CG15835 influences heterochromatin organization, but is excluded from heterochromatin. Overexpression of dJMJD2(1)/CG15835 does not affect the pattern of H3K9me2,3 at heterochromatin. dJMJD2(1)/CG15835 localizes to multiple euchromatic sites, where it mostly regulates H3K36me3, as its overexpression results in a strong decrease in the levels of H3K36me3. dJMJD2(1)/CG15835 regulates spreading of HP1
physiological function
H3K9me3 demethylase KDM4A/JMJD2A is able to increase accessibility and alter the replication timing at specific heterochromatic regions. KDM4A overexpression promotes copy gain of 1q12, 1q21, and Xq13.1 in cancer cells and results in site-specific copy gain of regions amplified in human tumors. These copy gains are not stably inherited but are generated transiently in each subsequent S phase and cleared by late G2. KDM4A is the only KDM4 family member that generated the gains in a catalytically dependent manner, copy gains are antagonized by coexpression of Suv39h1/KMT1A or HP1gamma, and promoted by H3K9 or H3K36 methylation interference. KDM4A associates with replication machinery and promotes rereplication of 1q12. KDM4A overexpression promotes chromatin state changes and recruitment of replication machinery. KDM4A-dependent 1q12h copy gain requires catalytic activity and Tudor domains, the KDM4A catalytic domain alone is insufficient to generate 1q12h gain
physiological function
histone demethylase Dmel\Kdm4A controls genes required for life span and male-specific sex determination in Drosophila melanogaster. Essential role for Dmel\Kdm4A in the transcriptional activation of genes involved in the aging process and male-specific neuronal formation and courtship behavior
physiological function
histone demethylases such as members of the Jumonji family revert histone trimethylation. Unlike other demethylases, JmjD2/KDM4 proteins have been shown to remove both lysine 9 and 36 trimethyl marks. Dynamic histone modifications are critical for proper temporal control of neural crest gene expression in vivo. The histone demethylase, JumonjiD2A (JmjD2A/KDM4A), is expressed in the forming neural folds. Direct stage-specific interactions of JmjD2A with regulatory regions of neural crest genes, associated temporal modifications in methylation states of lysine residues are directly affected by JmjD2A activity. Chromatin modifications directly control neural crest genes in vertebrate embryos via modulating histone methylation. JmjD2A plays an important role in neural crest development. H3K9me3 and H3K36me3 occupancy regulates neural crest specifier expression in vivo
physiological function
in mouse embryonic fibroblasts engineered for the inducible expression of KDM4B, upon inducing Kdm4b, H3K9/36me3 levels significantly decrease compared to non-induced controls, and H3K9me1 levels significantly increase, while H3K9me2 and H3K27me3 remain unchanged. Reduced H3K9/36me3 levels are restored after somatic nuclear transfer
physiological function
JMJD2A accelerates malignant progression of liver cancer cells in vitro and in vivo. Mechanistically, JMJD2A promotes the expression and mature of pre-miR372 epigenetically. Notably, miR372 blocks the editing of 13th exon-introns-14th exon and forms a novel transcript (JMJD2ADELTA) of JMJD2A. Enzyme JMJD2A is overexpressed in cancer and inhibits repair of DNA damage by reducing homologous recombination repair. Histone H3K36 trimethylation (H3K36me3) is associated with carcinogenesis. Histone H3 demethylase JMJD2A promotes growth of liver cancer cells, via Pim1-ppRB1-CDK2-CycinE-C-myc pathway, through upregulating miR372, JMJD2A enhances miR372 expression epigenetically, mechanism, overview. In particular, JMJD2A inhibits P21 (WAF1/Cip1) expression by decreasing H3K9me3 dependent on JMJD2ADELTA. JMJD2A enhances Pim1 transcription by suppressing P21(WAF1/Cip1) involving altered histone H3 lysine 9 methylation. Furthermore, through increasing the expression of Pim1, JMJD2A facilitates the interaction among pRB, CDK2 and CyclinE which prompts the transcription and translation of oncogenic C-myc. JMJD2A may trigger the demethylation of Pim1
physiological function
Jmjd2a and Jmjd2c both localize to H3K4me3-positive promoters, where they have widespread and redundant roles in preventing accumulation of H3K9me3 and H3K36me3. Jmjd2 catalytic activity is required for embryonic stem cell (ESC) maintenance. Jmjd2a and Jmjd2c are essential for early embryonic development. Recruitment of the Jmjd2 H3K9/H3K36 demethylases to H3K4me3-marked nucleosomes. Jmjd2a and Jmjd2c redundantly regulate histone methylation levels
physiological function
JMJD2A is implicated in transcriptional silencing and is associated with the retinoblastoma protein, class I HDACs, and the nuclear corepressor N-CoR. JMJD2A and its paralogue JMJD2D associate with the androgen receptor (AR) to upregulate the expression of AR-dependent genes. The transcriptional functions of JMJD2 enzymes appear to be context-dependent
physiological function
KDM4A overexpression promotes chromatin state changes and recruitment of replication machinery and leads to localized copy gain of cytogenetic bands 1q12, 1q21, and Xq13.1 without global chromosome instability. KDM4A-amplified tumors have increased copy gains for these same regions. 1q12h copy gain occurs within a single cell cycle, requires S phase and is not stable but regenerated each cell division. Sites with increased copy number are rereplicated and have increased KDM4A, MCM and DNA polymerase occupancy. Suv39h1/KMT1A or HP1gamma overexpression suppresses the copy gain, while H3K9/K36 methylation interference promotes gain
physiological function
KDM4A specifically demethylates H3K36me2 and me3 both in vitro and in vivo. Heterochromatin Protein 1a (HP1a) associates with KDMA4A. The chromoshadow domain of HP1a and a HP1-interacting motif of KDM4A are responsible for this interaction. HP1a stimulates the histone H3K36 demethylation activity of dKDM4A. Loss of HP1a leads to increased level of histone H3K36me3
physiological function
KdmA, a histone H3 demethylase with bipartite function, differentially regulates primary and secondary metabolism in Aspergillus nidulans. KdmA displays locus-specific histone H3 lysine demethylation activity
physiological function
levels of H3K4me modulate temperature sensitive alleles of the transcriptional elongation complex Spt6-Spn1. The Rpd3S histone deacetylase complex is the H3K4me effector underlying these Spt6-Spn1 genetic interactions. H3K4 and H3K36 demethylases JHD2 and RPH1 mediate this combinatorial control of Rpd3S histone deacetylase complex
physiological function
overexpression of JHDM3A abrogates recruitment of HP1 (heterochromatin protein 1) to heterochromatin. Knockdown of JHDM3A leads to increased levels of H3K9 methylation and upregulation of JHDM3A target gene ASCL2
physiological function
overexpression of JMJD2A reduces H3-K9/K36 trimethylation levels in cultured cells
physiological function
overexpression of Rph1 reduces the expression of photoreactivation gene PHR1 and increases UV sensitivity. Rph1 is associated at the upstream repression sequence of PHR1 through zinc-finger domains and is dissociated after UV irradiation. Overexpression of Rph1 and H3K36A mutant reduces histone acetylation at the URS. Protein Rad53 acts as an upstream regulator of Rph1 and dominates the phosphorylation of Rph1 that is required for efficient PHR1 expression and the dissociation of Rph1
physiological function
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papillomaviruses DNA is histone-associated in infected cells. Reducing H3K36me3 by overexpression of KDM4A blocks productive viral replication. H3K36me3 is enriched on the 3' end of the early region of the high-risk papillomavirus HPV31 genome in a SETD2-dependent manner
physiological function
reducing H3K36me3 levels by overexpressing KDM4A reduces homologous recombination repair events. Tumor suppressor SETD2 is also required for homologous recombination repair events
physiological function
RNAi depletion results in an increase in general trimethylation of H3-K9 and localizes H3-K36Me3 levels on meiotic chromosomes and triggers p53-dependent germline apoptosis
physiological function
Rph1 functions as a specific demethylase for H3 K36me3 and K36me2, directly regulating Lys36 methylation in transcribed regions. Both JmjC-domain proteins Jhd1 and Rph1 are required for normal levels of RNA polymerase II crosslinking to genes. Overexpression of either Jhd1 or Rph1 bypasses the requirement for the positive elongation factor gene BUR1
physiological function
Rph1 is mainly a transcriptional repressor, more than 75% of Rph1-regulated genes show increased expression in the Rph1-deletion mutant. The binding motif 5'-CCCCTWA-3' is overrepresented in the promoters of Rph1-repressed genes. A significant proportion of Rph1-regulated genes respond to DNA damage and environmental stress. Rph1 is a labile protein, and Rad53 negatively modulates Rph1 protein level. The JmjN domain is important in maintaining protein stability and the repressive effect of Rph1
physiological function
the histone lysine demethylase KDM4A regulates H3K9 and H3K36 methylation states
physiological function
the JmjC histone lysine demethylases (KDMs) are epigenetic regulators involved in the removal of methyl groups from post-translationally modified lysyl residues within histone tails, modulating gene transcription
physiological function
various types of human cancers exhibit amplification or deletion of KDM4A-D members, which selectively demethylate H3K9 and H3K36, thus implicating their activity in promoting carcinogenesis
physiological function
catalyzes the demethylation of di- and trimethylated Lys9 (reactions of EC 1.14.11.65 and 1.14.11.66) and Lys36 in histone H3 (reactions of EC 1.14.11.27 and 1.14.11.69). Jmjd2a responds to 5-hydroxytryptamine and promotes the expression of the brain-derived neurotrophic factor (Bdnf), a protein critically involved in neuropathic pain. JMJD2A binds to the promoter of Bdnf and demethylates H3K9me3 and H3K36me3 at the Bdnf promoter to promote the expression of Bdnf. JMJD2A promotes the expression of Bdnf during neuropathic pain and neuron-specific knockout of Jmjd2a blocks the hypersensitivity of mice undergoing chronic neuropathic pain
physiological function
depletion of KDM4A in prostate cancer cells inhibits their proliferation and survival in vivo and vitro. Deubiquitinase USP1 regulates KDM4A K48-linked deubiquitination and stability. c-Myc is a key downstream effector of the USP1-KDM4A/androgen receptor axis in driving prostate cancer cell proliferation. Upregulation of KDM4A expression with high USP1 expression is observed in most prostate tumors and inhibition of USP1 promotes prostate cancer cells response to therapeutic agent enzalutamide
physiological function
histone H3.3 G34R substitution mutation, found in paediatric gliomas, causes widespread changes in H3K9me3 and H3K36me3 level by interfering with the KDM4 family of K9/K36 demethylases. Expression of a targeted single-copy of H3.3 G34R at endogenous levels induces chromatin alterations that are comparable to a KDM4 isoforms A/B/C triple-knockout. H3.3 G34R preferentially binds KDM4 while simultaneously inhibiting its enzymatic activity
physiological function
JMJD2A displays higher expression in glioma tissues than that in normal brain tissues and lower levels of H3K9me3/H3K36me3 are found in glioma tissues. Knockdown of JMJD2A expression attenuates the growth and colony formation in glioma cell lines U251, T98G, and U87MG, whereas JMJD2A overexpression results in opposing effects. JMJD2A knockdown reduces the growth of glioma T98G cells in vivo. JMJD2A activates the Akt-mTOR pathway and promotes protein synthesis in glioma cells via promoting phosphoinositide-dependent kinase-1 expression
physiological function
KDM4 activity is required for hematopoietic stem cell (HSC) maintenance in vivo. The combined knockout of Kdm4a, Kdm4b, and Kdm4c leads to reduction of myeloid and lymphoid cells. In conditional KDM4A/B/C triple-knockout mice, the knockout leads to accumulation of H3K9me3 on transcription start sites and the corresponding downregulation of expression of several genes in HSCs. Genes Taf1b and Nom1, are essential for the maintenance of hematopoietic cells
physiological function
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histone H3K36 demethylase Rph1/KDM4 regulates the expression of the photoreactivation gene PHR1, the demethylation at H3K36 is linked to UV sensitivity. Overexpression of Rph1 and H3K36A mutant reduced histone acetylation at the URS, which implies a crosstalk between histone demethylation and acetylation at the PHR1 promoter. Rph1 is a repressor of the DNA repair gene PHR1. Rph1 is dissociated from the PHR1 promoter in response to DNA damage. Rad53 regulates the expression of PHR1 and dissociation of Rph1 in response to DNA damage. Activated Rad53 complex phosphorylates Rph1 and S652A-mutated Rph1 impairs the dissociation in response to DNA damage
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physiological function
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Rph1 might be a regulatory node connecting different signaling pathways responding to environmental stresses. Rph1 is mainly a transcriptional repressor. Rph1-regulated genes respond to DNA damage and environmental stress. Microarray analysis, overview
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physiological function
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KdmA, a histone H3 demethylase with bipartite function, differentially regulates primary and secondary metabolism in Aspergillus nidulans. KdmA displays locus-specific histone H3 lysine demethylation activity
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physiological function
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KdmA, a histone H3 demethylase with bipartite function, differentially regulates primary and secondary metabolism in Aspergillus nidulans. KdmA displays locus-specific histone H3 lysine demethylation activity
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physiological function
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KdmA, a histone H3 demethylase with bipartite function, differentially regulates primary and secondary metabolism in Aspergillus nidulans. KdmA displays locus-specific histone H3 lysine demethylation activity
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physiological function
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Jmjd2a and Jmjd2c both localize to H3K4me3-positive promoters, where they have widespread and redundant roles in preventing accumulation of H3K9me3 and H3K36me3. Jmjd2 catalytic activity is required for embryonic stem cell (ESC) maintenance. Jmjd2a and Jmjd2c are essential for early embryonic development. Recruitment of the Jmjd2 H3K9/H3K36 demethylases to H3K4me3-marked nucleosomes. Jmjd2a and Jmjd2c redundantly regulate histone methylation levels
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physiological function
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KdmA, a histone H3 demethylase with bipartite function, differentially regulates primary and secondary metabolism in Aspergillus nidulans. KdmA displays locus-specific histone H3 lysine demethylation activity
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physiological function
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KdmA, a histone H3 demethylase with bipartite function, differentially regulates primary and secondary metabolism in Aspergillus nidulans. KdmA displays locus-specific histone H3 lysine demethylation activity
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additional information
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a modest increase in global H3K36me3 levels is compatible with viability, fertility, and the expression of most genes, whereas decreased H3K36me3 levels are detrimental in males
additional information
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Rph1 is a labile protein, and Rad53 negatively modulates Rph1 protein level. The JmjN domain is important in maintaining protein stability and the repressive effect of Rph1. Binding motif 5'-CCCCTWA-3', which resembles the stress response element, is overrepresented in the promoters of Rph1-repressed genes. JmjN and ZF domains of Rph1 are required for its function. Rph1 binds to gene promoters and is dissociated with DNA damage
additional information
cellular demethylase activity of KDM4A demonstrates a graded response to oxygen concentration in U2OS cells. Analysis of the H3K27me3 (cf. EC 1.14.11.68) mark shows loss of this mark upon overexpression of KDM4A in normoxia, with a graded response to oxygen similar to that seen for H3K9me3, although less-pronounced. H3K27me3 is not a canonical substrate for KDM4A, hence, loss of this mark cannot be directly attributed to catalytic KDM4A activity. Effect of oxygen availability on the activity of the KDM4 subfamily member KDM4A, overview. A high level of O2 sensitivity both with isolated protein and in cells is observed
additional information
enzyme structure-function relationships and substrate selectivity, comparisons of KDM4 enzymes, overview
additional information
enzyme structure-function relationships and substrate selectivity, comparisons of KDM4 enzymes, overview
additional information
enzyme structure-function relationships and substrate selectivity, comparisons of KDM4 enzymes, overview
additional information
in H3K9me3- and H3K36me3-enzyme complexes, the peptides bind in the same directionality within the substrate binding cleft of JMJD2A, depositing the trimethyllysines into the active site. The majority of the interactions between the enzyme and H3 peptides involve hydrogen bond and van der Waals interactions with the backbone atoms in the substrates. The residues N-terminal to the trimethyllysines adopt a similar beta-strand-like conformation, while the C-terminal residues in the peptides adopt distinct binding modes. Mono-, di-, and trimethyllysines bind within a methylammonium binding pocket adjacent to the Fe(II) and 2-oxoglutarate binding sites in JMJD2A. This pocket is lined with an array of oxygen atoms that participate in direct contacts with zeta-methyl groups of the trimethylated substrate. Structure-activity analysis, overview
additional information
interaction between JMJD2A and substrate peptides largely involves the main chains of the enzyme and the peptide. The peptide-binding specificity is primarily determined by the primary structure of the peptide, which explains the specificity of JMJD2A for methylated H3K9 and H3K36 instead of other methylated residues such as H3K27. The specificity for a particular methyl group is affected by multiple factors, such as space and the electrostatic environment in the catalytic center of the enzyme. Mechanisms and specificity of histone demethylation, overview. Residues Q86, N88, D135, and Y175 are involved in the interaction with the peptide, whereas residues Y177, N290, S288, and T289 are involved in methyl group binding. K241 is proposed to recruit the O2 molecule into the catalytic center. Glycine residues at +3 or +4 in the substrate are essential for substrate specificity
additional information
residue S288 modulates the methylation-state specificities of JMJD2 enzymes and other trimethyllysine-specific JmjC HDMs. The mechanisms by which JMJD2A discriminates against the demethylation of H3K4me and H4K20me. An alignment of the H3K4, H3K9, H3K36 and H4K20 methylation sites reveals substantial sequence diversity among the methylation motifs. The methylammonium-binding pocket is composed of the carbonyl oxygen of Gly170, the hydroxyl groups of Tyr177 and Ser288, and the carboxylate side chain of Glu190. Active site site structure with bound substrate, overview
additional information
the mechanism for achieving methylation state selectivity involves the orientation of the substrate methyl groups towards a ferryl intermediate. Active site structure and mechanism of JMJD2A, overview