The Roles of Jumonji-Type Oxygenases in Human Disease

Figures & data

Figure 1.  Phylogenetic tree of the human 2-oxoglutarate-dependent oxygenases.

Different subfamilies discussed in the text are highlighted in various colors. Red asterisks indicate members for which no enzymatic activity has been determined yet.

Figure 2.  The overall fold of the catalytic JmjC domain in iron- and 2-oxoglutarate-dependent histone demethylases and nucleotide hydroxylases.

(A) Jmj prototype member JmjD2A (PDB ID: 2OQ7) in complex with Ni²⁺ (which replaces the endogenous Fe²⁺) and the 2-oxoglutarate competitive inhibitor N-oxalyl glycine (NOG). The double-stranded β-helical core elements are labeled I–VIII and colored cyan, the additional β-strands in blue and the helices in red. Ni²⁺ is shown as a green sphere and NOG as yellow sticks. (B) Overlay of the catalytic core (displayed are the active site metal, the Glu-His triad of active site residues and NOG) of human JmjD2A (green) compared to human ALKBH2 (PDB ID: 3BTX; light blue), indicating similar folding patterns of the catalytic domain. (C) Catalytic core of human methyladenosine demethylase FTO (PDB ID: 3LFM [14]) demonstrating the double-stranded β-helical fold and including the active site metal (blue sphere).

Table 1.  Domain organization and substrates of human Jmj-type oxygenases.

Name	Domain architecture	Histone substrate	Nonhistone substrate	Ref.
KDM2
FBXL10		H3K36me1/me2, H3K4me3	Unknown	[15,16]
FBXL11		H3K36me1/me2	p65, NF-κB	[15,17]
KDM3
JmjD1A		H3K9me2/me1	Unknown	[18,19]
JmjD1B		H3K9me2/me1	Unknown	[18,19]
JmjD1C		Unknown	Unknown	[19]
HR		Unknown	Unknown
KDM4
JmjD2A		H3K9me2/me3, H3K36me2/me3, H1.4K26me2/me3	Trimethylated lysine from chromatin repressor WIZ, CDYL1, CSB and G9a proteins	[20–22]
JmjD2B		H3K9me2/me3, H3K36me2/me3, H1.4K26me2/me3	Trimethylated lysine from chromatin repressor WIZ, CDYL1, CSB and G9a proteins	[20–22]
JmjD2C		H3K9me2/me3, H3K36me2/me3, H1.4K26me2/me3	Trimethylated lysine from chromatin repressor WIZ, CDYL1, CSB and G9a proteins	[20–22]
JmjD2D		H3K9me2/me3, H1.4K26me2/me3	Unknown	[20, 22]
JmjD2E		H3K9me2/me3, H1.4K26me2/me3	Unknown	[20]
JmjD2F		Unknown	Unknown
KDM5
JARID1A		H3K4me1/me2/me3	Unknown	[23–27]
JARID1B		H3K4me1/me2/me3	Unknown	[23–27]
JARID1C		H3K4me1/me2/me3	Unknown	[23–27]
JARID1D		H3K4me1/me2/me3	Unknown	[23–27]
JARID2		No enzymatic activity defined	Unknown
KDM6
UTX		H3K27me2/me3	Unknown	[28–32]
UTY		Unknown	Unknown
JmjD3		H3K27me2/me3	Unknown	[28–32]
KDM7
PHF2		H3K9me2	Unknown	[33]
PHF8		H3K9me2/me1, H4K20me1	Unknown	[34–38]
KIAA1718		H3K9me2/me1, H3K27me1/me2	Unknown	[34]
Hydroxylases
NO66		H3K4me1/me2/me3 H3K36me2/me3	Rpl8	[39, 40]
MINA53		H3K9me3	Rpl27a	[39, 41]
JmjD4		Unknown	Unknown
JmjD5/KDM8		H3K36me2/me1	NFATc1 hydroxylation	[42, 43]
JmjD6		H3R2me2,H4R3me2/me1, H2A/H2B, H3/H4	U2AF2/U2AF65, LUC7L2	[44–47]
JmjD7		Unknown	Unknown
JmjD8		Unknown	Unknown
FIH		Unknown	HIF-1α; ARD-containing proteins	[48–51]
HSPBAP1		Unknown	Unknown
TYW5		Unknown	tRNA^Phe	[52]
Nucleotide hydroxylases
ALKBH1		Unknown	Dealkylation of 1-methyladenosine and 3-methylcytosine in single-stranded DNA	[53, 54]
ALKBH2		Unknown	Dealkylation of 1-methyladenosine and 3-methylcytosine in single-stranded DNA	[53, 54]
ALKBH3		Unknown	Dealkylation of 1-methyladenosine and 3-methylcytosine in single-stranded DNA	[53, 54]
ALKBH4		Unknown	Lysine demethylation in actin (murine)	[55]
ALKBH5		Unknown	Methyl-6-adenine	[56]
ALKBH6		Unknown	Unknown
ALKBH7		Unknown	Unknown
ALKBH8		Unknown	tRNA	[57]
TET1		Unknown	Oxidation of 5-methylcytosine and formation of 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxycytosine	[58, 59]
TET2		Unknown	Oxidation of 5-methylcytosine and formation of 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxycytosine	[58, 59]
TET3		Unknown	Oxidation of 5-methylcytosine and formation of 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxycytosine	[58, 59]
FTO		Unknown	Methyluracil, methylthymine, demethylation of N6-methyladenosine	[60, 61]

Table 2.   Involvement of Jmj-type demethylases and other oxygenases in human physiology and disease.

Member	Subfamily	Function		Human physiology and disease
			Development	Cancer	Inflammation	Other
KDM2
FBXL11; FBXL10	KDM2	H3K36me2/1 demethylase; regulation of CGI epigenetic environment;	Role in reprogramming, pluripotency and maintenance of stem cell properties [97–102]	[106–108]	Regulation of NFκB activity by demethylation of Lys residue in NFκB [17]	–
KDM3
JmjD1A	KDM3A	H3K9me2/1 demethylase; coactivator of AR transcription	Sperm development (mouse knockout model) [112,113]	Overexpression in cancer cells [117] bladder, lung, hepatocellular [118], prostate [119], colorectal [120] and renal cell carcinoma [121]	–	Obese phenotype (mouse knockout model) [112,113], transcriptional control of metabolic genes in muscle and adipose tissue [114,115]
JmjD1B	KDM3B	H3K9me2/1 demethylase; interaction with transcriptional repressors	–	Putative tumor suppressor [19,124–125]; frequently deleted in myeloid leukemias [122] and in breast cancer [123]	–	–
JmjD1C	–	Interaction with thyroid hormone receptor	–	Putative role in tumor suppression [129]	–	–
HR	–	Corepressor for several nuclear receptors (thyroid hormone, retinoic acid and vitD); interaction with HDAC	–	–	–	Mutations are associated with congenital alopecia or atrichia with papular lesions [131,138]
KDM4
JmjD2A	KDM4A	H3K9/H3K36 demethylase; coregulator for nuclear receptors such as AR	Neural crest development [156]; cardiac hypertrophy [157] (murine model studies)	Role in progression of hormone responsive and hormone nonresponsive cancers (prostate, breast) [142–145]	–	–
JmjD2B	KDM4B	H3K9/H3K36 demethylase; coregulator for nuclear receptors such as AR	Mesenchymal stem cell differentiation [158] (murine model system)	Role in progression of hormone responsive and hormone nonresponsive cancers (prostate, breast) [142–145]; regulation of AR stability [146,147]; overexpressed in ER-positive primary breast cancer [151–153]	–	–
JmjD2C	KDM4C	H3K9/H3K36 demethylase; coregulator for nuclear receptors such as AR	–	Role in progression of hormone responsive and hormone nonresponsive cancers (prostate, breast) [142–145]; amplified in triple-negative (estrogen, progesterone and HER2 receptors) breast cancers [148]	–	–
JmjD2D	KDM4D	H3K9me3/2 and H1.4K26me3 demethylase	–	Interaction with p53 [161] and CAR [160]	Control of immune-cell specific enhancer elements by H3K9me3 demethylation [155]	Regulation of drug metabolism (murine) [160]
KDM5
JARID1A	KDM5A	H3K4 demethylase	Control of developmental genes (e.g., HOX) [23]	NUP98/JARID1A gene fusion involved in pediatric AMKL [169], determinant of drug resistance [171]	Susceptibility gene in ankylosing spondylitis [170]	–
JARID1B	KDM5B	H3K4 demethylase	Stem cell maintenance and differentiation [172–174]	control of cellular senescence [167]; regulation of tumor suppression/breast cancer cells [175,177]; melanoma [176]; cancer stem cell maintenance [178,179]	–	–
JARID1C	KDM5C	H3K4 demethylase	XLID [180]; ASD [182]; regulation of neuronal genes [164]	Tumor growth suppression through interaction with VHL protein [183]	–	–
JARID1D	KDM5D	H3K4 demethylase	Genomic locus is associated with AZF region [187]	Deleted in 50% of prostate cancer [188]	–	Male-specific histocompatibility antigen (H-Y) [184–186];
KDM6
UTX	KDM6A	Regulation of H3K27 repressive marks, scaffolding function for chromatin complexes	Kabuki syndrome [208,209]	Inactivating somatic mutations in multiple tumor types [233]	–	–
JmjD3	KDM6B	Regulation of H3K27 repressive marks, scaffolding function for chromatin complexes	Regulation of key developmental genes [196–199]	Tumor suppressor function through activation of P16/INK4a and p14/ARF locus [226–228]. Overexpression associated with oncogenic function found in multiple tumor types [211,220–223], [224,225]. Oncogenic role in EMT [229–231]. Mutations found in ALL [232].	Macrophage plasticity (mouse) [213,214]; and proinflammatory gene regulation [28,189,210]; T helper cell development [191]; possible target in SLE [215]; overexpression in vasculitis [218]	–
UTY	–	Enzymatic activity unknown, scaffolding function for chromatin complexes	–	–	–	Graft/host interaction, minor HLA-B8 antigen [235]; risk factor in cardiovascular disease [236]
KDM7
KIAA1718	KDM7A	Transcriptional coactivator; removal of repressive histone marks	Regulation of neural differentiation e.g., through control of FGF4 [245]	–	–	–
PHF8	KDM7B	Transcriptional coactivator; removal of repressive histone marks	Siderius-Hamel syndrome; XLMR, cleft-lip/cleft palate [247–249]; autism spectrum disorders [251,252]	RARα coactivation in promyelocytic leukemia [243]	–	–
PHF2	KDM7C	Transcriptional coactivator; removal of repressive histone marks	–	–	Control of proinflammatory gene expression [244]	Breast cancer [246]
Other hydroxylases
MINA53	–	Ribosome modification, chromatin hydroxylation/demethylation?	–	Dysregulation in various cancers [263,267,269–270,273,279]; direct target of c-myc	Allergen response [274]; TH17 cell development [275]	–
NO66	–	Ribosome modification; histone demethylation	Regulation of MSC–osteoblast differentiation [40]	Overexpression in non-small-cell lung cancer [279]	–	–
JmjD4	–	Function unknown
JmjD5	–	Histone modification? Interaction with p53, effect on proliferation; hydroxylation of transcription factors	Growth retardation, ablation is embryonically lethal (murine) [281,282]; regulation of transcription factor half-life through hydroxylation [43].	Overexpression in leukemia and breast cancer [281]	–	Involvement in control of circadian rhythm [280].
JmjD6	–	Presumably involved in RNA splicing and/or metabolism, lysine 5-hydroxylation [45,285]	From murine models: Critical for normal development of multiple tissues such as brain, eyes, lung, kidney, liver and intestine [286–288]; ablation of its function is associated with complex cardiopulmonary malformations resembling tetralogy of Fallot [289]	Overexpression linked to poor prognosis in breast cancer [290]; lung adenocarcinoma [92]	–	–
JmjD7	–	Unknown function	–	–	–	–
JmjD8	–	Unknown activity; inhibition of proliferation and cell invasion	–	Model system for squamous cell carcinoma [292]	–	–
FIH	–	Regulation of hypoxic response	–	FIH expression is regulated by microRNA-31 in head and neck squamous cell carcinoma [257]; prognostic factor for poor overall survival in clear cell renal cell carcinoma [258]	–	FIH-null mice display metabolic changes (reduced body weight, elevated metabolic rate and resistance to effects of high-fat diet) [255,256]
HSPBAP	–	Unknown enzymatic function	–	–	–	Differential expression in intractable epilepsy (neuron, glial cells) [296,297]; neuroprotective function [295,296]
TYW5	–	tRNA hydroxylation	–	–	–	–
Nucleotide hydroxylases
FTO	–	RNA N^6-methyladenosine demethylase; demethylation of methylthymine and methyluracil	Regulation of energy homeostasis; increased postnatal lethality, growth retardation, microcephaly, psychomotor delay, dysmorphism, cleft palate, cardiac abnormalities [325]	Breast cancer [323]; colorectal cancer [324]	–	Insulin resistance, obesity [318,319]; Alzheimer’s disease [320]; cardiovascular disease [321]; end-stage renal disease [322]
TET1	–	Hydroxylation of methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxycytosine	Cell differentiation, embryonic development [329]	Myeloproliferative neoplasms, CMML and AML [327–328,330]	–	–
TET2	–	Same as TET1	Cell differentiation, embryonic development [329]	Myeloproliferative neoplasms, CMML and AML [327–328,330]	–	–
TET3	–	Same as TET1	Cell differentiation, embryonic development [329]	Myeloproliferative neoplasms, CMML and AML [327–328,330]	–	–
ALKBH1	–	DNA and RNA; repair of alkylated nucleotides	–	Non-small-cell lung cancer [306]	–	–
ALKBH2	–	DNA and RNA; repair of alkylated nucleotides	–	Regulation of cell-cycle and EMT in urothelial carcinoma [305]; drug resistance in glioblastoma [307]; cancer risk in meningioma [304]	–	–
ALKBH3	–	DNA and RNA; repair of alkylated nucleotides	–	Tumor survival function in lung, pancreas, urothelial, prostate carcinoma [308–311]	–	–
ALKBH4	–	Function unknown	–	–	–	–
ALKBH5	–	RNA N^6-methyladenosine demethylase	Impaired spermatocyte development (mouse) [56]	–	–	Genetic locus for obesity in hispanic population [331]
ALKBH6	–	Function unknown	–	–	–	–
ALKBH7	–	Function unknown	–	–	–	–
ALKBH8	–	tRNA synthesis, methyltransferase	–	Bladder cancer progression [326]	–	–

Note that several functions in physiology are inferred from animal model studies. For subfamily annotation see Figure 1. AML: Acute myeloid leukemia; AMKL: Acute megakaryoblastic leukemia; AR: Androgen receptor; AZF: Azoospermia factor; CAR: Constitutive androstane receptor; CGI: CpG island; CMML: Chronic myelomonocytic leukemia; ER: Estrogen receptor; HDAC: Histone deacetylase; MSC: Mesenchymal stem cell; SLE: Systemic lupus erythematosus; vitD: Vitamin D; XLID: X-linked intellectual disability; XLMR: X-linked mental retardation.

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