KDM6A

Official Full Name

lysine demethylase 6A

Organism

Homo sapiens

GeneID

7403

Background

This gene is located on the X chromosome and is the corresponding locus to a Y-linked gene which encodes a tetratricopeptide repeat (TPR) protein. The encoded protein of this gene contains a JmjC-domain and catalyzes the demethylation of tri/dimethylated histone H3. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Apr 2014]

Synonyms

UTX; KABUK2; bA386N14.2;

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Detailed Information

Recent research

Epigenetic regulation of immunity and inflammation has now attracted a lot of attention. The discovery of histone H3K27me3 demethylase, lysine demethylase 6A (KDM6A) (UTX) and 6B (JMJD3) increases our understanding of how methylation kinetics are regulated. Preliminary studies have found that KDM6A is localized to the transcription initiation site of the Hox gene, in which knockdown of KDM6A in zebrafish leads to misregulation of Hox genes and post-developmental defects.

KDM6A contains 29 exons and is one of the X chromosome genes, most of which escape X inactivation. Since both KMT2D and KDM6A are histone modification factors, other pathogenic genes of KS may have functions associated with these two genes. KMT2D and KDM6A have been proposed to counteract the epigenetic control of transcriptionally active chromatin by counteracting the combination of Polycomb histones.

Functional studies have shown that homozygous mutations in KDM6A in mice result in severe midgestational defects, delayed development, neural tube closure, yolk bags and heart defects. In addition, KDM6A-deficient embryonic stem cells showed failure of the cardiac differentiation program. KDM6A was also found to be involved in the mixed lineage leukemia histone methyltransferase and trithorax histones involved in gene activation.

In 2016, a study using genome-wide analysis to compare the high and low reproductive populations of Chinese Laoshan dairy goats found that several genes have potential key effects on fertility, including lysine demethylase 6A (KDM6A), androgen receptor (AR) and anti-Muller disease. Among these genes, KDM6A encodes a protein that trimethylates histone H3 and demethylates dimethylated lysine 27, and can affect gametophyte development. Importantly, many studies have confirmed that the KDM6A gene is critical for animal reproduction. In rodents, knockout of the KDM6A gene disrupts the development of primordial germ cells.

Recently, six KMT2D-mutant negative KS patients have been reported to have deletion or nonsense single nucleotide variation in KDM6A (previous UTX) (histone H3 lysine 27 (H3K27)-specific demethylase). The KDM6A transcript is 5.4 Kb and translated into a 154 kDa protein. KDM6A removes the H3K27me3 marker associated with gene silencing. KDM6A binds to KMT2D and several other proteins, including RBBP5, DPY30, WDR5, MATR3, ASH2L, NSD1, PAXIP1, NCOA6 and c16orf53, in complexes involved in the regulation of various downstream gene expression.

The KDM6A gene was identified as the second causative gene of KS, and de novo deletions and point mutations in the KDM6A coding region have been identified in 9-13% of KMT2D-negative KS patients. KDM6A mutations have been widely observed. Phenotypic profiles range from typical KS to milder clinical manifestations. That is, K12 with a deletion shows a typical KS phenotype. Specific manifestations include long cleft palate, short nasal septum and eversion, short stature, abnormal heart, severe mental retardation, repeated infections and Chiari malformations.

Evidence of the association of a given pathway with a PPI (protein-protein interaction) network derived from KDM6A was examined. Some scholars have studied the KDM6A PPI network diagram. The network consists of 74 nodes connected by 453 edges. KDM6A has seven direct neighbors, RBBP5, WDR5, ASH2L, MLL2, PAXIP1, NCOA6 and RBL2. KDM6A contains a tetrapeptide motif that predicts protein-protein interactions and is not only a member of a stable multiprotein complex that demethylates H3K27me3, but also a MLL2 H3K4 methyltransferase complex that promotes genes expression. Its catalytic activity is related to the regulation of the homeobox (HOX) and RB transcription networks. Different protein partners regulate the recruitment of KDM6A to specific chromatin regions to target specific genes. There are three clusters whose nodes are distinguished by different colors in the network. There is a connection between these clusters.

KDM6A Figure 1. PPI network of KDM6A.

The PPI network from KDM6A presents a panoramic view that helps to understand the role of KDM6A. The results of path identification and network ontology analysis confirm and complement each other. Systematic evaluation of a gene by a network approach is a useful approach. Given that these may be non-specific interactions, the network can only be considered a guide map.

References:

Hemming S , et al. EZH2 and KDM6A act as an Epigenetic Switch to Regulate Mesenchymal Stem Cell Lineage Specification. Stem Cells, 2014, 32(3).
Li X , et al. Demethylase Kdm6a epigenetically promotes IL-6 and IFN-β production in macrophages. Journal of Autoimmunity, 2017:S0896841116303602.
Cheon C K , et al. Identification of KMT2D and KDM6A mutations by exome sequencing in Korean patients with Kabuki syndrome. Journal of Human Genetics, 2014, 59(6):321-325.
Banka S , et al. Novel KDM6A ( UTX ) mutations and a clinical and molecular review of the X﹍inked Kabuki syndrome ( KS2 ). Clinical Genetics, 2015, 87(3):252-258.

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