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FLASH GENE

Symbol

KDM6A

contributors: mct - updated : 18-03-2015

HGNC name	lysine (K)-specific demethylase 6A
HGNC id	12637

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
SPECIAL FEATURE	escaping inactivation
text	escaping inactivation
STRUCTURE	239.43 kb     29 Exon(s)

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_021140 29 splicing 5778 NP_066963 154.2 1401 - 1998 9499428

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Lymphoid/Immune thymus       highly Respiratory respiratory tract trachea     highly

cell lineage

cell lines

fluid/secretion

at STAGE

IMPRINTING
text	escaping X chromosome inactivation (expressed from the inactive X chromosome)

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	catalytic jumonji domain binding H3 AAs 25-33, recognizing H3R26, H3A29, and H3P30 in a sequence-specific manner, in addition to H3K27me3 in the catalytic pocket
	a zinc-binding domain, conserved within the KDM6 family, binding AAs 17-21 of H3
	eight TPR (tetratricopeptide repeat)
	one JmjC domain in the C-terminal half

conjugated

PhosphoP

HOMOLOGY

interspecies	homolog to rattus Utx (96.6pc)
	homolog to murine Kdm6a (97.5pc)

intraspecies

paralog to UTY

Homologene

FAMILY

UTX family

CATEGORY

regulatory

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm
	intracellular,nucleus

basic FUNCTION	having a histone demethylase function (histone H3K27-specific demethylase)
	occuping the promoters of HOX gene clusters and regulating their transcriptional output by modulating the recruitment of polycomb repressive complex 1 (PRC1) and the monoubiquitination of histone H2A
	may be involved in anterior-posterior development
	mediates demethylation of H3K27me3 at muscle-specific genes (MYOG, CKM) during myogenesis (Seenundun 2010)
	enables retinoblastoma-dependent cell fate control (Wwang 2010)
	encodes histone H3 lysine 27 (H3K27) demethylase
	having a function in the transcriptional regulation of RB1 and RBL2 that play important roles in cell proliferation
	existed in the multi-protein complex associated with the RB1 and RBL2 promoters, but might play a unique role in each complex for transcriptional regulation
	H3K27 demethylases, KDM6B and KDM6A, mediate a functional interaction between the lineage-defining T-box transcription factor family and a SMARCA4-containing SWI/SNF remodeling complex
	H3K27 demethylase, acting as a critical switch to promote a cardiac-specific gene program
	key roles for UTX in a timely transition from poised to active chromatin in cardiac genes during heart development
	is a novel mediator with distinct functions during the re-establishment of pluripotency and germ cell development
	required for embryonic development in a sex-specific manner
	H3K27 demethylation and specifically KDM6B and KDM6A catalytic activity are critical determinants of proinflammatory gene activation in human primary macrophages
	regulates mesoderm differentiation and Brachyury expression independent of its enzymatic activity
	escaping X inactivation, is implicated in the regulation of genes important in reproduction, suggesting that KDM6A may play a role in the etiology of developmental and reproduction-related effects of X chromosome anomalies
	early embryonic H3K27me3 repression can be alleviated in the absence of active demethylation by KDM6A, KDM6B
	KDM6B and KDM6A are required for T-cell development, and point to a requirement for their H3K27Me3 demethylase activity in cell differentiation
	mediates removal of repressive trimethylation of histone H3 lysine 27 (H3K27me3) to establish transcriptionally permissive chromatin
	critical role for the enzymatic activity of KDM6A in activating muscle-specific gene expression during myofiber regeneration
	both KDM6A and UTY function as dose-dependent suppressors of urothelial bladder cancer (UBC) development

CELLULAR PROCESS

nucleotide, transcription, regulation

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

associating with MLL3 and MLL4-containing histone H3K4 methyltransferase complex(es)

INTERACTION

DNA	directly binding to the HOXB1 locus and is required for its activation

RNA

small molecule	cofactor,
	ascorbate
	Fe2+

protein	associating with the H3K4me3 histone methyl transferase MLL2
	interacting with TLE1
	interacting with RB and RBL2 (RB and RBL2 are downstream target genes of KDM6A and may play important roles in KDM6A-mediated cell growth control)
	MLL2-interacting protein
	KDM6A and KDM6B contribute to the activation of WNT3 and DKK1 at different differentiation stages when WNT3 and DKK1 are required for mesendoderm and definitive endoderm differentiation, respectively
	controls mesoderm differentiation and Brachyury (T) expression independent of H3K27 demethylase activity, suggesting that KDM6A and UTY are functionally redundant in ES cell differentiation and early embryonic development
	chromatin regulators EP300, KDM5A, KDM6A and KDM6B cooperate with KLF4 in promoting the transcription of POU5F1
	through cooperation with POLR2A and KDM6A, SUPT6H orchestrates removal of H3K27me3, thus controlling developmental gene expression and cell differentiation
	both EZH2 and KDM6A were shown to affect expression of master regulatory genes involved in adipogenesis and osteogenesis and H3K27me3 on the promoters of master regulatory genes

cell & other

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

KMS3

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral somatic mutation       inactivating somatic mutations, pointing to H3Lys methylation deregulation in multiple tumor types (Van Haaften 2009) constitutional   translocation     with haploinsufficiency of KDM6A is associated with severe psychomotor retardation, global growth restriction, seizures and cleft palate

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer     KDM6A reintroduction into cancer cells with inactivating mutations resulted in slowing of proliferation and marked transcriptional changes

ANIMAL & CELL MODELS

	Utx-null embryos had reduced somite counts, neural tube closure defects and heart malformation that presented between E9.5 and E13.5
	male Utx-null mice escape embryonic lethality due to expression of UTY, a paralog that lacks H3K27 demethylase activity, suggesting an enzyme-independent role for UTX in development and thereby challenging the need for active H3K27 demethylation