Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Human UTY(KDM6C) is a male-specific N?-methyl lysyl demethylase.

ABSTRACT: The Jumonji C lysine demethylases (KDMs) are 2-oxoglutarate- and Fe(II)-dependent oxygenases. KDM6A (UTX) and KDM6B (JMJD3) are KDM6 subfamily members that catalyze demethylation of N(?)-methylated histone 3 lysine 27 (H3K27), a mark important for transcriptional repression. Despite reports stating that UTY(KDM6C) is inactive as a KDM, we demonstrate by biochemical studies, employing MS and NMR, that UTY(KDM6C) is an active KDM. Crystallographic analyses reveal that the UTY(KDM6C) active site is highly conserved with those of KDM6B and KDM6A. UTY(KDM6C) catalyzes demethylation of H3K27 peptides in vitro, analogously to KDM6B and KDM6A, but with reduced activity, due to point substitutions involved in substrate binding. The results expand the set of human KDMs and will be of use in developing selective KDM inhibitors.

SUBMITTER: Walport LJ

PROVIDER: S-EPMC4140284 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Human UTY(KDM6C) is a male-specific Nϵ-methyl lysyl demethylase.

Walport Louise J LJ Hopkinson Richard J RJ Vollmar Melanie M Madden Sarah K SK Gileadi Carina C Oppermann Udo U Schofield Christopher J CJ Johansson Catrine C

The Journal of biological chemistry 20140505 26

The Jumonji C lysine demethylases (KDMs) are 2-oxoglutarate- and Fe(II)-dependent oxygenases. KDM6A (UTX) and KDM6B (JMJD3) are KDM6 subfamily members that catalyze demethylation of N(ϵ)-methylated histone 3 lysine 27 (H3K27), a mark important for transcriptional repression. Despite reports stating that UTY(KDM6C) is inactive as a KDM, we demonstrate by biochemical studies, employing MS and NMR, that UTY(KDM6C) is an active KDM. Crystallographic analyses reveal that the UTY(KDM6C) active site is ...[more]

PMID: 24798337

Similar Datasets

Inhibitors of both the N-methyl lysyl- and arginyl-demethylase activities of the JmjC oxygenases.

Project description:The Jumonji C (JmjC) family of 2-oxoglutarate (2OG)-dependent oxygenases have established roles in the regulation of transcription via the catalysis of demethylation of Nε-methylated lysine residues in histone tails, especially the N-terminal tail of histone H3. Most human JmjC Nɛ -methyl lysine demethylases (KDMs) are complex enzymes, with 'reader domains' in addition to their catalytic domains. Recent biochemical evidence has shown that some, but not all, JmjC KDMs also have Nω-methyl arginyl demethylase (RDM) activity. JmjC KDM activity has been linked to multiple cancers and some JmjC proteins are therapeutic targets. It is, therefore, important to test not only whether compounds in development inhibit the KDM activity of targeted JmjC demethylases, but also whether they inhibit other activities of these proteins. Here we report biochemical studies on the potential dual inhibition of JmjC KDM and RDM activities using a model JmjC demethylase, KDM4E (JMJD2E). The results reveal that all of the tested compounds inhibit both the KDM and RDM activities, raising questions about the in vivo effects of the inhibitors.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.

| S-EPMC5915715 | biostudies-literature

UTX and UTY demonstrate histone demethylase-independent function in mouse embryonic development.

Project description:UTX (KDM6A) and UTY are homologous X and Y chromosome members of the Histone H3 Lysine 27 (H3K27) demethylase gene family. UTX can demethylate H3K27; however, in vitro assays suggest that human UTY has lost enzymatic activity due to sequence divergence. We produced mouse mutations in both Utx and Uty. Homozygous Utx mutant female embryos are mid-gestational lethal with defects in neural tube, yolk sac, and cardiac development. We demonstrate that mouse UTY is devoid of in vivo demethylase activity, so hemizygous X(Utx-) Y(+) mutant male embryos should phenocopy homozygous X(Utx-) X(Utx-) females. However, X(Utx-) Y(+) mutant male embryos develop to term; although runted, approximately 25% survive postnatally reaching adulthood. Hemizygous X(+) Y(Uty-) mutant males are viable. In contrast, compound hemizygous X(Utx-) Y(Uty-) males phenocopy homozygous X(Utx-) X(Utx-) females. Therefore, despite divergence of UTX and UTY in catalyzing H3K27 demethylation, they maintain functional redundancy during embryonic development. Our data suggest that UTX and UTY are able to regulate gene activity through demethylase independent mechanisms. We conclude that UTX H3K27 demethylation is non-essential for embryonic viability.

| S-EPMC3459986 | biostudies-literature

Male germ cell-specific knockout of cholesterogenic cytochrome P450 lanosterol 14?-demethylase (Cyp51).

Project description:Cytochrome P450 lanosterol 14?-demethylase (CYP51) and its products, meiosis-activating sterols (MASs), were hypothesized by previous in vitro studies to have an important role in regulating meiosis and reproduction. To test this in vivo, we generated a conditional male germ cell-specific knockout of the gene Cyp51 in the mouse. High excision efficiency of Cyp51 allele in germ cells resulted in 85-89% downregulation of Cyp51 mRNA and protein levels in germ cells. Quantitative metabolic profiling revealed significantly higher levels of CYP51 substrates lanosterol and 24,25-dihydrolanosterol and substantially diminished levels of MAS, the immediate products of CYP51. However, germ cell-specific ablation of Cyp51, leading to lack of MAS, did not affect testicular morphology, daily sperm production, or reproductive performance in males. It is plausible that due to the similar structures of cholesterol intermediates, previously proposed biological function of MAS in meiosis progression can be replaced by some other yet-unidentified functionally redundant lipid molecule(s). Our results using the germ cell-specific knockout model provide first in vivo evidence that the de novo synthesis of MAS and cholesterol in male germ cells is most likely not essential for spermatogenesis and reproduction and that MASs, originating from germ cells, do not cell-autonomously regulate spermatogenesis and fertility.

| S-EPMC3646466 | biostudies-literature

Crystal structure of human histone lysine-specific demethylase 1 (LSD1).

Project description:Lysine-specific demethylase 1 (LSD1) was recently identified as the first histone demethylase that specifically demethylates monomethylated and dimethylated histone H3 at K4. It is a component of the CoREST and other corepressor complexes and plays an important role in silencing neuronal-specific genes in nonneuronal cells, but the molecular mechanisms of its action remain unclear. The 2.8-A-resolution crystal structure of the human LSD1 reveals that LSD1 defines a new subfamily of FAD-dependent oxidases. The active center of LSD1 is characterized by a remarkable 1,245-A3 substrate-binding cavity with a highly negative electrostatic potential. Although the protein core of LSD1 resembles other flavoenzymes, its enzymatic activity and functions require two additional structural modules: an N-terminal SWIRM domain important for protein stability and a large insertion in the catalytic domain indispensable both for the demethylase activity and the interaction with CoREST. These results provide a framework for further probing the catalytic mechanism and the functional roles of LSD1.

| S-EPMC1599895 | biostudies-literature

Human Sex Matters: Y-Linked Lysine Demethylase 5D Drives Accelerated Male Craniofacial Osteogenic Differentiation.

Project description:Female sex is increasingly associated with a loss of bone mass during aging and an increased risk of developing nonunion fractures. Hormonal factors and cell-intrinsic mechanisms are suggested to drive these sexual dimorphisms, although underlying molecular mechanisms are still a matter of debate. Here, we observed a decreased capacity of calvarial bone recovery in female rats and a profound sexually dimorphic osteogenic differentiation in human adult neural crest-derived stem cells (NCSCs). Next to an elevated expression of pro-osteogenic regulators, global transcriptomics revealed Lysine Demethylase 5D (KDM5D) to be highly upregulated in differentiating male NCSCs. Loss of function by siRNA or pharmacological inhibition of KDM5D significantly reduced the osteogenic differentiation capacity of male NCSCs. In summary, we demonstrated craniofacial osteogenic differentiation to be sexually dimorphic with the expression of KDM5D as a prerequisite for accelerated male osteogenic differentiation, emphasizing the analysis of sex-specific differences as a crucial parameter for treating bone defects.

| S-EPMC8909072 | biostudies-literature

Human lysyl oxidase-like 2.

Project description:Lysyl oxidase like-2 (LOXL2) belongs to the lysyl oxidase (LOX) family, which comprises Cu(2+)- and lysine tyrosylquinone (LTQ)-dependent amine oxidases. LOXL2 is proposed to function similarly to LOX in the extracellular matrix (ECM) by promoting crosslinking of collagen and elastin. LOXL2 has also been proposed to regulate extracellular and intracellular cell signaling pathways. Dysregulation of LOXL2 has been linked to many diseases, including cancer, pro-oncogenic angiogenesis, fibrosis and heart diseases. In this review, we will give an overview of the current understandings and hypotheses regarding the molecular functions of LOXL2.

| S-EPMC6309629 | biostudies-literature

Lysine-specific demethylase 2A (KDM2A) normalizes human embryonic stem cell derived keratinocytes.

Project description:Studies on human lysine-specific demethylase 2A (KDM2A) by others have recently begun. To date, the demethylase activity has been known to reduce expression of genes and eventually inhibit proliferation of cells. However, while attempting to improve proliferation of hES-cell-derived Nod keratinocytes, which grow poorly and have a short life span, we found that high expression of the KDM2A gene improves the poor proliferation of the cells. Of the four isomer cDNAs that we prepared from alternatively spliced KDM2A transcripts, only one stimulates the proliferation. This (KDM2A-N782) encodes the 782AA protein containing the JmjC, CXXC, and Ring domains, but not the F-box and AMN1 domains, unlike KDM2A, which has been studied by other groups. Our results not only show that differently spliced transcripts from a gene result in totally opposite outcomes, but also present critical evidence of the complicated activities of KDM2A, which contains all of the five domains.

| S-EPMC3386085 | biostudies-literature

Sex-specific differences in expression of histone demethylases Utx and Uty in mouse brain and neurons.

Project description:Although X inactivation is thought to balance gene expression between the sexes, some genes escape inactivation, potentially contributing to differences between males and females. Utx (ubiquitously transcribed tetratricopeptide repeat gene on X chromosome) is an escapee gene that encodes a demethylase specific for lysine 27 of histone H3, a mark of repressed chromatin. We found Utx to be expressed higher in females than in males in developing and adult brains and in adult liver. XX mice had a higher level of Utx than XY mice, regardless of whether they had testes or ovaries, indicating that the sexually dimorphic gene expression was a consequence of the sex chromosome complement. Females had significantly higher levels of Utx than males in most brain regions except in the amygdala. The regional expression of the Y-linked paralogue Uty (ubiquitously transcribed tetratricopeptide repeat gene on Y chromosome) was somewhat distinct from that of Utx, specifically in the paraventricular nucleus of the hypothalamus (high Uty) and the amygdala (high Utx), implying that the two paralogues may be differentially regulated. Higher expression of Utx compared with Uty was detected in P19 pluripotent embryonic carcinoma cells as well as in P19-derived neurons. This transcriptional divergence between the two paralogues was associated with high levels of histone H3 lysine 4 dimethylation at the Utx promoter and of histone H4 lysine 16 acetylation throughout the gene body, which suggests that epigenetic mechanisms control differential expression of paralogous genes.

| S-EPMC2643472 | biostudies-literature

Histone lysine specific demethylase 1 inhibitors.

Project description:LSD1 plays a pivotal role in numerous biological functions. The overexpression of LSD1 is reported to be associated with different malignancies. Over the last decade, LSD1 has emerged as an interesting target for the treatment of acute myeloid leukaemia (AML). Numerous researchers have designed, synthesized, and evaluated various LSD1 inhibitors with diverse chemical architectures. Some of these inhibitors have entered clinical trials and are currently at different phases of clinical evaluation. This comprehensive review enlists recent research developments in LSD1 targeting pharmacophores reported over the last few years.

| S-EPMC7513387 | biostudies-literature

Lysine-specific demethylase 1 inhibitors prevent teratoma development from human induced pluripotent stem cells.

Project description:Human induced pluripotent stem cells (hiPSCs) are creating great expectations for regenerative medicine. However, safety strategies must be put in place to guard against teratoma formation after transplantation of hiPSC-derived cells into patients. Recent studies indicate that epigenetic regulators act at the initial step of tumorigenesis. Using gain-of-function and loss-of-function approaches, we show here that the expression and function of lysine-specific demethylase 1 (LSD1) are tightly regulated in hiPSCs, and their deregulation underlies the development of teratomas. Consistent with these results, we demonstrate that an LSD1 inhibitor, S2157, prevented teratoma formation from hiPSCs transplanted into immunodeficient mice. This novel action of LSD1 and the effects of its inhibition potentially allow for the development of new clinical applications and therapeutic strategies using hiPSCs.

| S-EPMC5814224 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data