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Review
. 2020 Sep 28;40(20):e00341-20.
doi: 10.1128/MCB.00341-20. Print 2020 Sep 28.

Lysine Demethylase KDM6A in Differentiation, Development, and Cancer

Nhien Tran  1 , Aaron Broun  1 , Kai Ge  2
Affiliations
Review

Lysine Demethylase KDM6A in Differentiation, Development, and Cancer

Nhien Tran et al. Mol Cell Biol. .

Abstract

Lysine demethylase 6A (KDM6A), also known as UTX, belongs to the KDM6 family of histone H3 lysine 27 (H3K27) demethylases, which also includes UTY and KDM6B (JMJD3). The KDM6A protein contains six tetratricopeptide repeat (TPR) domains and an enzymatic Jumonji C (JmjC) domain that catalyzes the removal of di- and trimethylation on H3K27. KDM6A physically associates with histone H3 lysine 4 monomethyltransferases MLL3 (KMT2C) and MLL4 (KMT2D). Since its identification as an H3K27 demethylase in 2007, studies have reported KDM6A's critical roles in cell differentiation, development, and cancer. KDM6A is important for differentiation of embryonic stem cells and development of various tissues. Mutations of KDM6A cause Kabuki syndrome. KDM6A is frequently mutated in cancers and functions as a tumor suppressor. KDM6A is redundant with UTY and functions largely independently of its demethylase activity. It regulates gene expression, likely through the associated transcription factors and MLL3/4 on enhancers. However, KDM6A enzymatic activity is required in certain cellular contexts. Functional redundancy between H3K27 demethylase activities of KDM6A and KDM6B in vivo has yet to be determined. Further understanding of KDM6A functions and working mechanisms will provide more insights into enhancer regulation and may help generate novel therapeutic approaches to treat KDM6A-related diseases.

Keywords: H3K27 demethylase; KDM6A; KDM6A/UTX/H3K27 demethylase/enhancer regulation/gene expression; UTX; cancer; cell differentiation; development; enhancer regulation; gene expression.

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Figures

FIG 1
FIG 1
Trajectory of publication of KDM6A papers since the identification of the KDM6A gene in 1998. PubMed searches using keywords “kdm6a” and “utx” yielded more than 600 articles published from 1998 to 2019.
FIG 2
FIG 2
Schematic representation of the mouse KDM6 family of H3K27 demethylases, including KDM6A, KDM6B, and UTY. The catalytic JmjC domains and the TPR domains are indicated. KDM6A shares 83% protein sequence identity with its Y-linked homolog UTY. The C-terminal domain (amino acids [aa] 1174 to 1636) of KDM6B shares 70% protein sequence identity with KDM6A’s C-terminal domain (aa 931 to 1394).
FIG 3
FIG 3
The role of KDM6A in facilitating enhancer activation. KDM6A is recruited to the enhancer region by lineage-determining transcription factor (LDTF). KDM6A then facilitates the recruitment of the associated H3K4 methyltransferase MLL3/4 and other chromatin modifiers, including H3K27 acetyltransferase CBP/p300 and the SWI/SNF-dependent chromatin remodeler BRG1. This process promotes histone methylation, acetylation, and chromatin opening, which subsequently activates enhancers and turns on gene transcription.
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References

    1. Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y. 2004. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119:941–953. doi:10.1016/j.cell.2004.12.012. - DOI - PubMed
    1. Lan F, Bayliss PE, Rinn JL, Whetstine JR, Wang JK, Chen S, Iwase S, Alpatov R, Issaeva I, Canaani E, Roberts TM, Chang HY, Shi Y. 2007. A histone H3 lysine 27 demethylase regulates animal posterior development. Nature 449:689–694. doi:10.1038/nature06192. - DOI - PubMed
    1. Agger K, Cloos PA, Christensen J, Pasini D, Rose S, Rappsilber J, Issaeva I, Canaani E, Salcini AE, Helin K. 2007. UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature 449:731–734. doi:10.1038/nature06145. - DOI - PubMed
    1. Lee MG, Villa R, Trojer P, Norman J, Yan KP, Reinberg D, Di Croce L, Shiekhattar R. 2007. Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination. Science 318:447–450. doi:10.1126/science.1149042. - DOI - PubMed
    1. Hong S, Cho YW, Yu LR, Yu H, Veenstra TD, Ge K. 2007. Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases. Proc Natl Acad Sci U S A 104:18439–18444. doi:10.1073/pnas.0707292104. - DOI - PMC - PubMed

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