Aberrant levels of histone modifications lead to chromatin malfunctioning and consequently to various developmental defects and human diseases. Therefore, the proteins bearing the ability to modify histones have been extensively studied and the molecular mechanisms of their action are now fairly well understood. However, little attention has been paid to naturally occurring alternative isoforms of chromatin modifying proteins and to their biological roles. In this review, we focus on mammalian KDM2A and KDM2B, the only two lysine demethylases whose genes have been described to produce also an alternative isoform lacking the N-terminal demethylase domain. These short KDM2A/B-SF isoforms arise through alternative promoter usage and seem to play important roles in development and disease. We hypothesise about the biological significance of these alternative isoforms, which might represent a more common evolutionarily conserved regulatory mechanism.

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University and General University Hospital Prague Praha 2 Czech Republic

Zobrazit více v PubMed

Sen P, Shah PP, Nativio R, et al. Epigenetic Mechanisms of Longevity and Aging. Cell. 2016;166(4):822–839. PubMed PMC

Allshire RC, Madhani HD.. Ten principles of heterochromatin formation and function. Nat Rev Mol Cell Biol. 2018;19(4):229-244. PubMed PMC

Xu Q, Xie W. Epigenome in Early Mammalian Development: inheritance, Reprogramming and Establishment. Trends Cell Biol. 2018;28(3):237–253. PubMed

Gates LA, Foulds CE, O’Malley BW. Histone Marks in the ‘Driver’s Seat’: functional Roles in Steering the Transcription Cycle. Trends Biochem Sci. 2017;42(12):977–989. PubMed PMC

Atlasi Y, Stunnenberg HG. The interplay of epigenetic marks during stem cell differentiation and development. Nat Rev Genet. 2017;18(11):643–658. PubMed

Greer EL, Shi Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet. 2012;13(5):343–357. PubMed PMC

Allis CD, Jenuwein T. The molecular hallmarks of epigenetic control. Nat Rev Genet. 2016;17(8):487–500. PubMed

Kouzarides T. Chromatin modifications and their function. Cell. 2007;128(4):693–705. PubMed

Henikoff S, Smith MM. Histone variants and epigenetics. Cold Spring Harb Perspect Biol. 2015;7(1):a019364. PubMed PMC

Henikoff S, McKittrick E, Ahmad K. Epigenetics, histone H3 variants, and the inheritance of chromatin states. Cold Spring Harb Symp Quant Biol. 2004;69:235–243. PubMed

Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011;21(3):381–395. PubMed PMC

Berger SL. Histone modifications in transcriptional regulation. Curr Opin Genet Dev. 2002;12(2):142–148. PubMed

Li B, Carey M, Workman JL. The role of chromatin during transcription. Cell. 2007;128(4):707–719. PubMed

Tessarz P, Kouzarides T. Histone core modifications regulating nucleosome structure and dynamics. Nat Rev Mol Cell Biol. 2014;15(11):703–708. PubMed

Towbin BD, Gonzalez-Sandoval A, Gasser SM. Mechanisms of heterochromatin subnuclear localization. Trends Biochem Sci. 2013;38(7):356–363. PubMed

Cabianca DS, Gasser SM. Spatial segregation of heterochromatin: uncovering functionality in a multicellular organism. Nucleus. 2016;7(3):301–307. PubMed PMC

Palstra RJ, Grosveld F. Transcription factor binding at enhancers: shaping a genomic regulatory landscape in flux. Front Genet. 2012;3:195. PubMed PMC

Feng L, Zhu J, Chang H, et al. The CodY regulator is essential for virulence in Streptococcus suis serotype 2. Sci Rep. 2016;6:26597. PubMed PMC

Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012;150(1):12–27. PubMed

Hyun K, Jeon J, Park K, et al. Writing, erasing and reading histone lysine methylations. Exp Mol Med. 2017;49(4):e324. PubMed PMC

Helin K, Dhanak D. Chromatin proteins and modifications as drug targets. Nature. 2013;502(7472):480–488. PubMed

Foster CT, Dovey OM, Lezina L, et al. Lysine-specific demethylase 1 regulates the embryonic transcriptome and CoREST stability. Mol Cell Biol. 2010;30(20):4851–4863. PubMed PMC

Wang J, Scully K, Zhu X, et al. Opposing LSD1 complexes function in developmental gene activation and repression programmes. Nature. 2007;446(7138):882–887. PubMed

Metzger E, Wissmann M, Yin N, et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature. 2005;437(7057):436–439. PubMed

Shi Y, Lan F, Matson C, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell. 2004;119(7):941–953. PubMed

Wang J, Telese F, Tan Y, et al. LSD1n is an H4K20 demethylase regulating memory formation via transcriptional elongation control. Nat Neurosci. 2015;18(9):1256–1264. PubMed PMC

Laurent B, Ruitu L, Murn J, et al. A specific LSD1/KDM1A isoform regulates neuronal differentiation through H3K9 demethylation. Mol Cell. 2015;57(6):957–970. PubMed PMC

Jack APM, Bussemer S, Hahn M, et al. H3K56me3 is a novel, conserved heterochromatic mark that largely but not completely overlaps with H3K9me3 in both regulation and localization. PLoS One. 2013;8(2):e51765. PubMed PMC

Lange UC, Siebert S, Wossidlo M, et al. Dissecting the role of H3K64me3 in mouse pericentromeric heterochromatin. Nat Commun. 2013;4:2233. PubMed

Daujat S, Weiss T, Mohn F, et al. H3K64 trimethylation marks heterochromatin and is dynamically remodeled during developmental reprogramming. Nat Struct Mol Biol. 2009;16(7):777–781. PubMed

Kang J-Y, Kim J-Y, Kim K-B, et al. KDM2B is a histone H3K79 demethylase and induces transcriptional repression via sirtuin-1-mediated chromatin silencing. The FASEB Journal. 2018. doi:10.1096/fj.201800242R. PubMed

Shen H, Xu W, Lan F. Histone lysine demethylases in mammalian embryonic development. Exp Mol Med. 2017;49(4):e325. PubMed PMC

Pedersen MT, Helin K. Histone demethylases in development and disease. Trends Cell Biol. 2010;20(11):662–671. PubMed

Shi Y. Histone lysine demethylases: emerging roles in development, physiology and disease. Nat Rev Genet. 2007;8(11):829–833. PubMed

Klose RJ, Zhang Y. Regulation of histone methylation by demethylimination and demethylation. Nat Rev Mol Cell Biol. 2007;8(4):307–318. PubMed

Kooistra SM, Helin K. Molecular mechanisms and potential functions of histone demethylases. Nat Rev Mol Cell Biol. 2012;13(5):297–311. PubMed

Mozzetta C, Boyarchuk E, Pontis J, et al. Sound of silence: the properties and functions of repressive Lys methyltransferases. Nat Rev Mol Cell Biol. 2015;16(8):499–513. PubMed

Wiles ET, Selker EU. H3K27 methylation: a promiscuous repressive chromatin mark. Curr Opin Genet Dev. 2017;43:31–37. PubMed PMC

Eissenberg JC, Shilatifard A. Histone H3 lysine 4 (H3K4) methylation in development and differentiation. Dev Biol. 2010;339(2):240–249. PubMed PMC

Wagner EJ, Carpenter PB. Understanding the language of Lys36 methylation at histone H3. Nat Rev Mol Cell Biol. 2012;13(2):115–126. PubMed PMC

Farooq Z, Banday S, Pandita TK, et al. The many faces of histone H3K79 methylation. Mutat Res Rev Mutat Res. 2016;768:46–52. PubMed PMC

Nguyen AT, Zhang Y. The diverse functions of Dot1 and H3K79 methylation. Genes Dev. 2011;25(13):1345–1358. PubMed PMC

Nicholson TB, Chen T. LSD1 demethylates histone and non-histone proteins. Epigenetics. 2009;4(3):129–132. PubMed

Beh CY, El-Sharnouby S, Chatzipli A, et al. Roles of cofactors and chromatin accessibility in Hox protein target specificity. Epigenetics Chromatin. 2016;9(22):1–9. PubMed PMC

Okamoto K, Tanaka Y, Tsuneoka M. SF-KDM2A binds to ribosomal RNA gene promoter, reduces H4K20me3 level, and elevates ribosomal RNA transcription in breast cancer cells. Int J Oncol. 2017;50(4):1372〓1382. PubMed

Lađinović D, Novotná J, Jakšová S, et al. A demethylation deficient isoform of the lysine demethylase KDM2A interacts with pericentromeric heterochromatin in an HP1a-dependent manner. Nucleus. 2017;8(5):563–572. PubMed PMC

Liu H, Liu L, Holowatyj A, et al. Integrated genomic and functional analyses of histone demethylases identify oncogenic KDM2A isoform in breast cancer. Mol Carcinog. 2016;55(5):977–990. PubMed PMC

Long HK, Blackledge NP, Klose RJ. ZF-CxxC domain-containing proteins, CpG islands and the chromatin connection. Biochem Soc Trans. 2013;41(3):727–740. PubMed PMC

Tsukada Y, Fang J, Erdjument-Bromage H, et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature. 2006;439(7078):811–816. PubMed

Kolasinska-Zwierz P, Down T, Latorre I, et al. Differential chromatin marking of introns and expressed exons by H3K36me3. Nat Genet. 2009;41(3):376–381. PubMed PMC

Schwartz S, Meshorer E, Ast G. Chromatin organization marks exon-intron structure. Nat Struct Mol Biol. 2009;16(9):990–995. PubMed

Pickering T, Hamm JM, Page AF, et al. Cavity-free plasmonic nanolasing enabled by dispersionless stopped light. Nat Commun. 2014;5:4091. PubMed PMC

Pryde F, Jain D, Kerr A, et al. H3 k36 methylation helps determine the timing of cdc45 association with replication origins. PLoS One. 2009;4(6):e5882. PubMed PMC

Schmähling S, Meiler A, Lee Y, et al. Regulation and function of H3K36 di-methylation by the trithorax-group protein complex AMC. Development. 2018;145(7):1-11. PubMed PMC

Bell O, Wirbelauer C, Hild M, et al. Localised H3K36 methylation states define histone H4K16 acetylation during transcriptional elongation in Drosophila. EMBO J. 2007;26(24):4974–4984. PubMed PMC

Pokholok DK, Harbison CT, Levine S, et al. Genome-wide map of nucleosome acetylation and methylation in yeast. Cell. 2005;122(4):517–527. PubMed

Dhar SS, Alam H, Li N, et al. Transcriptional Repression of Histone Deacetylase 3 by the Histone Demethylase KDM2A Is Coupled to Tumorigenicity of Lung Cancer Cells. J Biol Chem. 2014;289(11):7483–7496. PubMed PMC

Wagner KW, Alam H, Dhar SS, et al. KDM2A promotes lung tumorigenesis by epigenetically enhancing ERK1/2 signaling. J Clin Invest. 2013;123(12):5231–5246. PubMed PMC

Janzer A, Stamm K, Becker A, et al. The H3K4me3 histone demethylase Fbxl10 is a regulator of chemokine expression, cellular morphology, and the metabolome of fibroblasts. J Biol Chem. 2012;287(37):30984–30992. PubMed PMC

Du J, Ma Y, Ma P, et al. Demethylation of epiregulin gene by histone demethylase FBXL11 and BCL6 corepressor inhibits osteo/dentinogenic differentiation. Stem Cells. 2013;31(1):126–136. PubMed

Yu G, Wang J, Lin X, et al. Demethylation of SFRP2 by histone demethylase KDM2A regulated osteo-/dentinogenic differentiation of stem cells of the apical papilla. Cell Prolif. 2016;49(3):330–340. PubMed PMC

He J, Kallin EM, Tsukada Y-I, et al. The H3K36 demethylase Jhdm1b/Kdm2b regulates cell proliferation and senescence through p15(Ink4b). Nat Struct Mol Biol. 2008;15(11):1169–1175. PubMed PMC

Tzatsos A, Pfau R, Kampranis SC, et al. Ndy1/KDM2B immortalises mouse embryonic fibroblasts by repressing the Ink4a/Arf locus. Proc Natl Acad Sci U S A. 2009;106(8):2641–2646. PubMed PMC

Chen J-Y, Li C-F, Chu P-Y, et al. Lysine demethylase 2A promotes stemness and angiogenesis of breast cancer by upregulating Jagged1. Oncotarget. 2016;7(19):27689–27710. PubMed PMC

Tsai C-L, Shi Y, Tainer JA. How substrate specificity is imposed on a histone demethylase-lessons from KDM2A. Genes Dev. 2014;28(16):1735–1738. PubMed PMC

Blackledge NP, Zhou JC, Tolstorukov MY, et al. CpG islands recruit a histone H3 lysine 36 demethylase. Mol Cell. 2010;38(2):179–190. PubMed PMC

Blackledge NP, Klose R. CpG island chromatin: a platform for gene regulation. Epigenetics. 2011;6(2):147–152. PubMed PMC

Farcas AM, Blackledge NP, Sudbery I, et al. KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands. Elife. 2012;1:e00205. PubMed PMC

Frescas D, Guardavaccaro D, Bassermann F, et al. JHDM1B/FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA genes. Nature. 2007;450(7167):309–313. PubMed

Tanaka Y, Okamoto K, Teye K, et al. JmjC enzyme KDM2A is a regulator of rRNA transcription in response to starvation. EMBO J. 2010;29(9):1510–1522. PubMed PMC

Gao R, Dong R, Du J, et al. Depletion of histone demethylase KDM2A inhibited cell proliferation of stem cells from apical papilla by de-repression of p15INK4B and p27Kip1. Mol Cell Biochem. 2013;379(12):115–122. PubMed

Frescas D, Guardavaccaro D, Kuchay SM, et al. KDM2A represses transcription of centromeric satellite repeats and maintains the heterochromatic state. Cell Cycle. 2008;7(22):3539–3547. PubMed PMC

Yamagishi T, Hirose S, Kondo T. Secondary DNA structure formation for Hoxb9 promoter and identification of its specific binding protein. Nucleic Acids Res. 2008;36(6):1965–1975. PubMed PMC

Rizwani W, Schaal C, Kunigal S, et al. Mammalian lysine histone demethylase KDM2A regulates E2F1-mediated gene transcription in breast cancer cells. PLoS One. 2014;9(7):e100888. PubMed PMC

Tanaka Y, Yano H, Ogasawara S, et al. Mild Glucose Starvation Induces KDM2A-Mediated H3K36me2 Demethylation through AMPK To Reduce rRNA Transcription and Cell Proliferation. Mol Cell Biol. 2015;35(24):4170–4184. PubMed PMC

Lu L, Gao Y, Zhang Z, et al. Kdm2a/b Lysine Demethylases Regulate Canonical Wnt Signaling by Modulating the Stability of Nuclear β-Catenin. Dev Cell. 2015;33(6):660–674. PubMed

Lu T, Jackson MW, Wang B, et al. Regulation of NF-kappaB by NSD1/FBXL11-dependent reversible lysine methylation of p65. Proc Natl Acad Sci U S A. 2010;107(1):46–51. PubMed PMC

Nusse R, Clevers H. Wnt/beta-Catenin Signaling, Disease, and Emerging Therapeutic Modalities. Cell. 2017;169(6):985–999. PubMed

Musselman CA, Kutateladze TG. Handpicking epigenetic marks with PHD fingers. Nucleic Acids Res. 2011;39(21):9061–9071. PubMed PMC

Taverna SD, Li H, Ruthenburg AJ, et al. How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat Struct Mol Biol. 2007;14(11):1025–1040. PubMed PMC

Zhou JC, Blackledge NP, Farcas AM, et al. Recognition of CpG island chromatin by KDM2A requires direct and specific interaction with linker DNA. Mol Cell Biol. 2012;32(2):479–489. PubMed PMC

Borgel J, Tyl M, Schiller K, et al. KDM2A integrates DNA and histone modification signals through a CXXC/PHD module and direct interaction with HP1. Nucleic Acids Res. 2017;45(3):1114–1129. PubMed PMC

Eissenberg JC, Elgin SCR. HP1a: a structural chromosomal protein regulating transcription. Trends Genet. 2014;30(3):103–110. PubMed PMC

Canzio D, Larson A, Narlikar GJ. Mechanisms of functional promiscuity by HP1 proteins. Trends Cell Biol. 2014;24(6):377–386. PubMed PMC

Kwon SH, Workman JL. The changing faces of HP1: from heterochromatin formation and gene silencing to euchromatic gene expression: HP1 acts as a positive regulator of transcription. Bioessays. 2011;33(4):280–289. PubMed

Maison C, Almouzni G. HP1 and the dynamics of heterochromatin maintenance. Nat Rev Mol Cell Biol. 2004;5(4):296–304. PubMed

Bannister AJ, Zegerman P, Partridge JF, et al. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature. 2001;410(6824):120–124. PubMed

Lachner M, O’Carroll D, Rea S, et al. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature. 2001;410(6824):116–120. PubMed

Cao LL, Wei F, Du Y, et al. ATM-mediated KDM2A phosphorylation is required for the DNA damage repair. Oncogene. 2016;35(3):301-313. PubMed

Panier S, Boulton SJ. Double-strand break repair: 53BP1 comes into focus. Nat Rev Mol Cell Biol. 2014;15(1):7–18. PubMed

Bueno MTD, Baldascini M, Richard S, et al. Recruitment of lysine demethylase 2A to DNA double strand breaks and its interaction with 53BP1 ensures genome stability. Oncotarget. 2018;9(22):15915–15930. PubMed PMC

Kipreos ET, Pagano M. The F-box protein family. Genome Biol. 2000;1(5):REVIEWS3002. PubMed PMC

Shen J, Spruck C. F-box proteins in epigenetic regulation of cancer. Oncotarget. 2017;8(66):110650–110655. PubMed PMC

Randle SJ, Laman H. F-box protein interactions with the hallmark pathways in cancer. Semin Cancer Biol. 2016;36:3–17. PubMed

Han X-R, Zha Z, Yuan H-X, et al. KDM2B/FBXL10 targets c-Fos for ubiquitylation and degradation in response to mitogenic stimulation. Oncogene. 2016;35(32):4179–4190. PubMed PMC

Blackledge NP, Farcas AM, Kondo T, et al. Variant PRC1 Complex-Dependent H2A Ubiquitylation Drives PRC2 Recruitment and Polycomb Domain Formation. Cell. 2014;157(6):1445–1459. PubMed PMC

Inagaki T, Iwasaki S, Matsumura Y, et al. The FBXL10/KDM2B scaffolding protein associates with novel polycomb repressive complex-1 to regulate adipogenesis. J Biol Chem. 2015;290(7):4163–4177. PubMed PMC

He J, Shen L, Wan M, et al. Kdm2b maintains murine embryonic stem cell status by recruiting PRC1 complex to CpG islands of developmental genes. Nat Cell Biol. 2013;15(4):373–384. PubMed PMC

Fukuda T, Tokunaga A, Sakamoto R, et al. Fbxl10/Kdm2b deficiency accelerates neural progenitor cell death and leads to exencephaly. Mol Cell Neurosci. 2011;46(3):614–624. PubMed

Liang G, He J, Zhang Y. Kdm2b promotes induced pluripotent stem cell generation by facilitating gene activation early in reprogramming. Nat Cell Biol. 2012;14(5):457–466. PubMed PMC

Wu X, Johansen JV, Helin K. Fbxl10/Kdm2b recruits polycomb repressive complex 1 to CpG islands and regulates H2A ubiquitylation. Mol Cell. 2013;49(6):1134–1146. PubMed

Dong R, Yao R, Du J, et al. Depletion of histone demethylase KDM2A enhanced the adipogenic and chondrogenic differentiation potentials of stem cells from apical papilla. Exp Cell Res. 2013;319(18):2874–2882. PubMed

Wang Z, Gearhart MD, Lee Y-W, et al. A Non-canonical BCOR-PRC1.1 Complex Represses Differentiation Programs in Human ESCs. Cell Stem Cell. 2018;22(2): 235–251. e9. PubMed PMC

Zhou Z, Yang X, He J, et al. Kdm2b Regulates Somatic Reprogramming through Variant PRC1 Complex-Dependent Function. Cell Rep. 2017;21(8):2160–2170. PubMed

Wang T, Chen K, Zeng X, et al. The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner. Cell Stem Cell. 2011;9(6):575–587. PubMed

Gonzalez I, Munita R, Agirre E, et al. A lncRNA regulates alternative splicing via establishment of a splicing-specific chromatin signature. Nat Struct Mol Biol. 2015;22(5):370–376. PubMed PMC

Kawakami E, Tokunaga A, Ozawa M, et al. The histone demethylase fbxl11/kdm2a plays an essential role in embryonic development by repressing cell-cycle regulators. Mech Dev. 2015;135:31–42. PubMed

Andricovich J, Kai Y, Peng W, et al. Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis. J Clin Invest. 2016;126(3):905–920. PubMed PMC

Boulard M, Edwards JR, Bestor TH. FBXL10 protects Polycomb-bound genes from hypermethylation. Nat Genet. 2015;47(5):479–485. PubMed

Huang Y, Liu Y, Yu L, et al. Histone demethylase KDM2A promotes tumor cell growth and migration in gastric cancer. Tumour Biol. 2015;36(1):271–278. PubMed

Chen J-Y, Luo C-W, Lai Y-S, et al. Lysine demethylase KDM2A inhibits TET2 to promote DNA methylation and silencing of tumor suppressor genes in breast cancer. Oncogenesis. 2017;6(8):e369. PubMed PMC

Pfau R, Tzatsos A, Kampranis SC, et al. Members of a family of JmjC domain-containing oncoproteins immortalise embryonic fibroblasts via a JmjC domain-dependent process. Proc Natl Acad Sci U S A. 2008;105(6):1907–1912. PubMed PMC

Batie M, Druker J, D’Ignazio L, et al. KDM2 Family Members are Regulated by HIF-1 in Hypoxia. Cells. 2017;6(1):8–16. PubMed PMC

Tzatsos A, Paskaleva P, Ferrari F, et al. KDM2B promotes pancreatic cancer via Polycomb-dependent and -independent transcriptional programs. J Clin Invest. 2013;123(2):727–739. PubMed PMC

Kuang Y, Lu F, Guo J, et al. Histone demethylase KDM2B upregulates histone methyltransferase EZH2 expression and contributes to the progression of ovarian cancer in vitro and in vivo. Onco Targets Ther. 2017;10:3131–3144. PubMed PMC

He J, Nguyen AT, Zhang Y. KDM2b/JHDM1b, an H3K36me2-specific demethylase, is required for initiation and maintenance of acute myeloid leukemia. Blood. 2011;117(14):3869–3880. PubMed PMC

Kottakis F, Foltopoulou P, Sanidas I, et al. NDY1/KDM2B functions as a master regulator of Polycomb complexes and controls self-renewal of breast cancer stem cells. Cancer Res. 2014;74(14):3935–3946. PubMed PMC

Banito A, Li X, Laporte AN, et al. The SS18-SSX Oncoprotein Hijacks KDM2B-PRC1.1 to Drive Synovial Sarcoma. Cancer Cell. 2018;33(3): 527–541. e8. PubMed PMC

De Klerk E, T Hoen PA. Alternative mRNA transcription, processing, and translation: insights from RNA sequencing. Trends Genet. 2015;31(3):128–139. PubMed

Davuluri RV, Suzuki Y, Sugano S, et al. The functional consequences of alternative promoter use in mammalian genomes. Trends Genet. 2008;24(4):167–177. PubMed

Vacik T, Raska I. Alternative intronic promoters in development and disease. Protoplasma. 2017;254(3):1201–1206. PubMed

Vacik T, Stubbs JL, Lemke G. A novel mechanism for the transcriptional regulation of Wnt signaling in development. Genes Dev. 2011;25(17):1783–1795. PubMed PMC

Vacik T, Lemke G. Dominant-negative isoforms of Tcf/Lef proteins in development and disease. Cell Cycle. 2011;10(24):4199–4200. PubMed

Kent WJ, Sugnet CW, Furey TS, et al. The human genome browser at UCSC. Genome Res. 2002;12(6):996–1006. PubMed PMC

Bartke T, Vermeulen M, Xhemalce B, et al. Nucleosome-interacting proteins regulated by DNA and histone methylation. Cell. 2010;143(3):470–484. PubMed PMC

Accari SL, Fisher PR. Emerging Roles of JmjC Domain-Containing Proteins. Int Rev Cell Mol Biol. 2015;319:165–220. PubMed

Landeira D, Fisher AG. Inactive yet indispensable: the tale of Jarid2. Trends Cell Biol. 2011;21(2):74–80. PubMed PMC

Dimitrova E, Kondo T, Feldmann A, et al. FBXL19 recruits CDK-Mediator to CpG islands of developmental genes priming them for activation during lineage commitment. Elife. 2018;7:1-27. PubMed PMC

Li MJ, Liu Z, Wang P, et al. GWASdb v2: an update database for human genetic variants identified by genome-wide association studies. Nucleic Acids Res. 2016;44:D869D876. PubMed PMC

Tak YG, Farnham PJ. Making sense of GWAS: using epigenomics and genome engineering to understand the functional relevance of SNPs in non-coding regions of the hum,an genome. Epigenetics Chromatin. 2015;8:57. PubMed PMC

Farh KK-H, Marson A, Zhu J, et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature. 2015;518(7539):337–343. PubMed PMC

Oldridge DA, Wood AC, Weichert-Leahey N, et al. Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism. Nature. 2015;528(7582):418–421. PubMed PMC

Zheng Y, Hsu F-N, Xu W, et al. A developmental genetic analysis of the lysine demethylase KDM2 mutations in Drosophila melanogaster. Mech Dev. 2014;133:36–53. PubMed PMC

Kavi HH, Birchler JA. Drosophila KDM2 is a H3K4me3 demethylase regulating nucleolar organization. BMC Res Notes. 2009;2:217. PubMed PMC

Lagarou A, Mohd-Sarip A, Moshkin YM, et al. dKDM2 couples histone H2A ubiquitylation to histone H3 demethylation during Polycomb group silencing. Genes Dev. 2008;22(20):2799–2810. PubMed PMC

Lysine Demethylase KDM2A Promotes Proteasomal Degradation of TCF/LEF Transcription Factors in a Neddylation-Dependent Manner

Alternative isoforms of KDM2A and KDM2B lysine demethylases negatively regulate canonical Wnt signaling