Histone Lysine Methylation
The level and state of histone lysine methylation depends not only on the activity of histone methyltransferases (KMTs) but also on the counteracting activity of histone lysine demethylases (KDMs). The variety of methylation sites and differentially methylated states describes the level of complexity of signaling mediated by histone lysine methylation, which is involved in transcription regulation, gene silencing, genome stability and RNA processing.
1. Histone Lysine Methylation
Epigenetic landscapes functionally define the chromatin architecture and they are shaped by the coordinated activity of “writers”, “readers” and “erasers”. “Writers” introduce covalent chemical modifications into DNA and histone tails, the “erasers” modulate the amount of these modifications and the “readers” recognize and bind the chemical modifications which induce functional effects in the chromatin architecture and DNA binding of transcription factors (TFs). Among the writers, histone methyltransferases catalyze the introduction of methyl groups in specific lysine and arginine residues at the amino terminal ends of the histone core , mainly at histones H3 and H4. Lysine methylation involves the ε-amine group of lysine at different positions of H3. Methylation events at K4, K9, K27, K36 and K79 are the most studied and characterized. Lysine can be mono-, di- or trimethylated. The level and state of histone lysine methylation depends not only on the activity of histone methyltransferases (KMTs) but also on the counteracting activity of histone lysine demethylases (KDMs). The variety of methylation sites and differentially methylated states describes the level of complexity of signaling mediated by histone lysine methylation, which is involved in transcription regulation, gene silencing, genome stability and RNA processing.
2. Histone Lysine 4 Methyltransferases
The enzymes responsible for histone lysine methylation (KMTs) contain a common active domain known as Su(var)3–9, Enhancer of zeste and Trithorax (SET), originally identified in yeast (SET1). Three SET1 homologs were subsequently identified in Drosophila melanogaster, including dSet1, Trithorax (Trx) and Trithorax-related , and 23 canonical SET-containing histone KMTs and one seven-beta-strand (7βS)-containing domain KMT (hDOT1L) with proven methyltransferase activity in mammals . Some KMTs are highly selective. Each KMT methylates a specific lysine but not others located at different positions in the H3 polypeptide chain. For instance, the KMT that methylates H3K36 does not methylate H3K4, and the only KMT able to methylate H3K79 is hDOT1L . In addition, a lysine can be specifically targeted by multiple enzymes. This redundancy allows specific activities to occur in a context-dependent manner. For instance, the same lysine may be modified by a different enzyme as a function of the histone’s genomic localization (enhancer versus promoter regions) but also to generate different methylation states (dimethylation versus trimethylation). KMT activity depends also on the specific lysine methylation state to add new methyl groups . H3K4 methylation is one of the most studied and characterized histone lysine methylations. H3K4 can be mono-(H3K4me1), di-(H3K4me2) or tri-(H3K4me3). In mammals, H3K4 methylation is catalyzed by six SET domain-containing KMTs, namely SET1A/KMT2F, SET1B/KMT2G, MLL1/KMT2A, MLL2/KMT2B, MLL3/KMT2C and MLL4/KMT2D. Each of these enzymes is a component of multimeric complexes that may or may not contain other proteins such as WDR5, RbBP5, ASH2L and DPY30 . These complexes are not redundant, as their activity marks H3K4 not only at functionally distinct loci but also at specific target genes determining different methylation states related to the recruitment of distinct “readers” . For instance, multimeric complexes containing MLL1 and MLL2 trimethylate H3K4 at the promoter region of Hox gene clusters, which require the correct transcriptional regulation for hematopoietic development . MLL2 is responsible for the tri-methylation of H3K4 of bivalent domains which is necessary for a mechanism aiming to maintain a paused transcriptional state in a targeted gene . MLL3 and MLL4 monomethylate H3K4 located at the enhancer regions involved in cell type-specific gene expression . Recent studies have revealed that the activity of KMT complexes is stimulated by the monoubiquitylation of histone H2B, and that distinct subunits components may have a role in determining the levels and state of H3K4 methylation .
3. Histone Lysine 4 Demethylases
To date, more than 30 KDM family members have been reported, and most of them contain a Jumonji domain, with the exception of KDM1A and KDM1B . As for KMTs, KDMs target methylated lysines in H3, mainly at K4, K27, K9, K36 and K56, and in H4 at K20. KDMs demethylate specific lysines and not others located in different positions of the histone polypeptide chain. For instance, H3K27me3 is demethylated by KDM6B, which is not able to demethylate H3K4me3. KDMs may have distinct genomic localization and biological effects . In mammals, H3K4 demethylation is catalyzed by the Jumonji, AT-rich interactive domain 1 (KDM5) and lysine-specific histone demethylase (KDM1) protein families. The KDM5 family is composed of four members designated KDM5A–D, and these enzymes are 2-oxoglutarate-dependent dioxygenases which require Fe2+ and O2 for their function in order to undergo the hydroxylation necessary to remove methyl groups . All members contain conserved domains of five types: the ARID (DNA-binding domain), C5HC2 zinc finger, Jumonji C (JmjC), Jumonji N (JmjN) and plant homeodomain finger (PHD) (histone-binding domain) domains . The KDM1 family is composed of the KDM1A member and its homolog, KDM1B, which are both Flavin Adenine Dinucleotide (FAD) -dependent histone lysine demethylases . The KDM1A consists of three domains: the amine oxidase domain, the FAD binding domain and the SWIRM domain. In particular, the FAD binding domain consists of a Tower domain, which interacts with RE1-Silencing Transcription factor (REST), a transcription factor essential for demethylation activity . KDM1B, however, does not bind REST . KDM5A-D and KDM1A-B proteins have histone demethylases activity towards particular histone H3K4 methylation states; for instance, KDM5A demethylates H3K4me3/2 and processively H3K4me1, and KDM1 demethylates H3K4me1/2, with KDM1A also demethylating H3K9 . KDM5A, KDM5C and KDM1A proteins form complexes with transcriptional repressors such as REST and KMTs establishing repressive chromatin marks . Members of the KDM5 andKDM1 families may differ in their functions and biological effects. The KDM5A-D proteins are associated with transcriptional repression, as H3K4me3 is considered to be a transcriptional activating signal, since it is globally distributed, mainly at the promoters of the transcribed genes, and seems fundamental for recruiting the preinitiation factor Transcription Factor IID (TFIID) to certain gene promoters, even if loss of H3K4me3 does not always affect gene transcription . However, KDM5A and B proteins may interact with different partners or complexes with transcriptional repressive functions such as Polycomb Repressive Complex 2 . KDM5A interacts with the SIN3B-containing deacetylase and the nucleosome remodeling and deacetylase (NuRD) complexes . KDM5B interacts with NuRD and KDM1A , whereas KDM5C interacts with the repressive H3K9 and H3K27 methyltransferase G9a in complex with histone deacetylases (HDACs) and REST . Moreover, KDM5B protein may interact directly with HDACs mediating their recruitment to specific sites . However, the activity of KDM5A–D also seems related, in some cases, to transcriptional activation, although it is not clear if this effect depends on demethylase activity or not . As for the KDM5 protein family, KDM1 demethylase activity is also related to transcriptional repression. However, KDM1A, as it can demethylate H3K9, may be associated with transcriptional activation . For instance, when KDM1A interacts with androgen and estrogen nuclear hormone receptors (AR and ER), it can demethylate H3K9me1/2, thus facilitating gene transcription . Moreover, a neuron-specific isoform of KDM1An (also known as LSD1n) can target H3K20me2 controlling transcriptional elongation of a neuronal gene network . Garcia-Bassets et al.  reported that 80% of the promoters occupied by KDM1A were bound to RNA polymerase II, suggesting that KDM1A was associated more often with active genes rather than the inactive genes. The formation of a protein complex including KDM1A, Rest corepressor (CoREST) and Growth factor independence (GFI) 1 proteins is also noteworthy . This complex target represses a gene regulatory network that is necessary for normal hematopoiesis. KDM1A–GFI interaction may be disrupted by pharmacological molecules rescuing blast cell differentiation in acute myeloid leukemia with MLL translocationsand restoring the normal H3K4me3 state at targeted gene promoters. KDM1A is also found to be associated with long non-coding RNAs (LncRNAs) such as HOX Transcript Antisense RNA(HOTAIR), TElomeric Repeat-containing RNA (TERRA) and Steroid receptor RNA activator (SRA) . Several non-histone proteins have been recognized as targets of KDM1A activity such as p53, MYPT1 , E2F1 , and HIF-1α , which determine different effects on protein stability. JARID1 and LSD demethylases are involved in various cellular processes, including cell proliferation, embryonic mesenchymal transition, stemness, differentiation, cell motility, autophagy and senescence , and their dysregulation is also closely associated with embryonic development , human cancer development and other diseases.
The entry is from 10.3390/biom11020143
- 1 Greer: E.L.; Shi, Y. Histone methylation: A dynamic mark in health, disease and inheritance. Nat. Rev. Genet. 2012, 13, 343–357.
- 2 Mohan, M.; Herz, H.-M.; Smith, E.R.; Zhang, Y.; Jackson, J.; Washburn, M.P.; Florens, L.; Eissenberg, J.C.; Shilatifard, A. The COMPASS Family of H3K4 Methylases in Drosophila. Mol. Cell. Biol. 2011, 31, 4310–4318.
- 3 Shilatifard, A. The COMPASS family of histone H3K4 methylases: Mechanisms of regulation in development and disease pathogenesis. Ann. Rev. Biochem. 2012, 81, 65–95.
- 4 Falnes, P.Ø.; Jakobsson, M.E.; Davydova, E.; Ho, A.; Małecki, J. Protein lysine methylation by seven-β-strand methyltransfer-ases. Biochem. J. 2016, 15, 1995–2009.
- 5 Husmann, D.; Gozani, O. Histone lysine methyltransferases in biology and disease. Nat. Struct. Mol. Biol. 2019, 26, 880–889.
- 6 Sun, X.J.; Wei, J.; Wu, X.-Y.; Hu, M.; et al. Identification and Characterization of a Novel Human Histone H3 Lysine 36-specific Methyltransferase. J. Biol. Chem. 2005, 280, 35261–35271.
- 7 Strahl, B.D.; Grant, P.A.; Briggs, S.D.; Sun, Z.-W.; Bone, J.R.; Caldwell, J.A.; Mollah, S.; Cook, R.G.; Shabanowitz, J.; Hunt, D.F.; et al. Set2 Is a Nucleosomal Histone H3-Selective Methyltransferase That Mediates Transcriptional Repression. Mol. Cell. Biol. 2002, 22, 1298–1306.
- 8 An, S.; Yeo, K.J.; Jeon, Y.H.; Song, J.-J. Crystal Structure of the Human Histone Methyltransferase ASH1L Catalytic Domain and Its Implications for the Regulatory Mechanism. J. Biol. Chem. 2011, 286, 8369–8374.
- 9 Ng, H.H.; Feng, Q.; Wang, H.; Erdjument-Bromage, H.; Tempst, P.; Zhang, Y.; Struhl, K. Lysine methylation within the glob-ular domain of histone H3 by Dot1 is important for telomeric silencing and Sir protein association. Genes Dev. 2002, 16, 1518–1527.
- 10 Feng, Q.; Wang, H.; Ng, H.H.; Erdjument-Bromage, H.; Tempst, P.; Struhl, K.; Zhang, Y. Methylation of H3-Lysine 79 Is Me-diated by a New Family of HMTases without a SET Domain. Curr. Biol. 2002, 12, 1052–1058.
- 11 Kuo, A.J.; Cheung, P.; Chen, K.; Zee, B.M.; Kioi, M.; Lauring, J.; Xi, Y.; Park, B.H.; Shi, X.; Garcia, B.A.; et al. NSD2 Links Dimethylation of Histone H3 at Lysine 36 to Oncogenic Programming. Mol. Cell 2011, 44, 609–620.
- 12 Edmunds, J. W.; Mahadevan, L. C.; Clayton, A. L. Dynamic histone H3 methylation during gene induction: HYPB/Setd2 mediates all H3K36 trimethylation. EMBO J. 2008, 27, 406–420.
- 13 Schotta, G.; Sengupta, R.; Kubicek, S.; Malin, S.; Kauer, M.; Callén, E.; Celeste, A.; Pagani, M.; Opravil, S.; De La Rosa-Velazquez, I.A.; et al. A chromatin-wide transition to H4K20 monomethylation impairs genome integrity and pro-grammed DNA rearrangements in the mouse. Genes Dev. 2008, 22, 2048–2061.
- 14 Beck, D. B.; Oda, H.; Shen, S. S.; Reinberg, D. PR-Set7 and H4K20me1: At the crossroads of genome integrity, cell cycle, chromosome condensation, and transcription. Genes Dev. 2012, 26, 325–337.
- 15 Kuo, A. J.; Song, J.; Cheung, P.; Ishibe-Murakami, S.; Yamazoe, S.; Chen, J.K.; Patel, D.J.; Gozani, O. The BAH domain of ORC1 links H4K20me2 to DNA replication licensing and Meier-Gorlin syndrome. Nature 2012, 484, 115–119.
- 16 Hyun, K.; Jeon, J.; Park, K.; Kim, J. Writing, erasing and reading histone lysine methylations. Exp. Mol. Med. 2017, 49, e324.
- 17 Crump, N.T. and Milne, T.A. Why are so many MLL lysine methyltransferases required for normal mammalian develop-ment? Cell. Mol. Life Sci. 2019, 76, 2885–2898.
- 18 Yang, W. and Ernst, P. Distinct functions of histone H3, lysine 4 methyltransferases in normal and malignant hematopoiesis. Curr. Opin. Hematol. 2017, 24, 322–328.
- 19 Yang, W. and Ernst, P. SET/MLL family proteins in hematopoiesis and leukemia. Int. J. Hematol. 2017, 105, 7–16.
- 20 Harikumar, A. and Meshorer, E. Chromatin remodeling and bivalent histone modifications in embryonic stem cells. EMBO Rep. 2015, 16, 1609–1619.
- 21 Jiang, Y.; Dominguez, P.M.; Melnick, A.M. The many layers of epigenetic dysfunction in B-cell lymphomas. Curr. Opin. He-matol. 2016, 23, 377–384.
- 22 Froimchuk, E.; Jang, Y. and Ge, K. Histone H3 lysine 4 methyltransferase KMT2D. Gene 2017, 627, 337–342.
- 23 Wang, C.; Lee, J.E.; Lai, B.; Macfarlan, T.S.; Xu, S.; Zhuang, L.; Liu, C.; Peng, W. and Ge, K. Enhancer priming by H3K4 me-thyltransferase MLL4 controls cell fate transition. Proc. Natl. Acad. Sci. USA 2016, 113, 11871–11876.
- 24 Lee, J.E.; Wang, C.; Xu, S.; Cho, Y.W.; Wang, L.; Feng, X.; Baldridge, A.; Sartorelli, V.; Zhuang, L.; Peng, W.; et al. H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. eLife 2013, 2, e01503.
- 25 Hu, D.; Gao, X.; Morgan, M.A.; Herz, H.M.; Smith, E.R. and Shilatifard, A. The MLL3/MLL4 branches of the COMPASs fam-ily function as major histone H3K4 monomethylases at enhancers. Mol. Cell. Biol. 2013, 33, 4745–4754.
- 26 Kwon, M.; Park, K.; Hyun, K.; Lee, J.-H.; Zhou, l.; Cho, Y.-W.; Ge, K.; Skalnik, D.G.; Muir, T.W.; Kim, J. H2B ubiquitylation enhances H3K4 methylation activities of human KMT2 family complexes. Nucl. Acids Res. 2020, 48, 5442–5456.
- 27 Shinsky, S.A.; Monteith, K.E.; Viggiano, S. and Cosgrove, M.S. Biochemical reconstitution and phylogenetic comparison of human SET1 family core complexes involved in histone methylation. J. Biol. Chem 2015, 290, 6361–6375.
- 28 Hsu, P.L.; Li, H.; Lau, H.T.; Leonen, C.; Dhall, A.; Ong, S.E.; Chatterjee, C. and Zheng, N. Crystal structure of the COMPASS H3K4 methyltransferase catalytic module. Cell 2018, 174, 1106–1116.
- 29 Shi, Y. G. and Tsukada, Y. The discovery of histone demethylases. Cold Spring Harb. Perspect. Biol. 2013, 5, a017947.
- 30 Kang, M.K.; Mehrazarin, S.; Park, N.-H. and Wang, C.-Y. Epigenetic gene regulation by histone demethylases: Emerging role in oncogenesis and inflammation. Oral Dis. 2017, 23, 709–720.
- 31 Højfeldt, J.W.; Agger, K.; Helin, K. Histone lysine demethylases as targets for anticancer therapy. Nat. Rev. Drug Discov. 2013, 12, 917–930.
- 32 Pilka, E.S.; James, T.; Lisztwan, J.H. Structural definitions of Jumonji family demethylase selectivity. Drug Discov. Today 2015, 20, 743–749.
- 33 Shi, Y.; Lan, F.; Matson, C.; Mulligan, P.; Whetstine, J.R.; Cole, P.A.; Casero, R.A. and Shi, Y. Histone demethylation mediat-ed by the nuclear amine oxidase homolog LSD1. Cell 2004, 119, 941–953.
- 34 Janardhan, A.; Kathera, C.; Darsi, A.; Ali, W.; He, L.; Yang, Y.; Luo, L.; Guo, Z. Prominent role of histone lysine demethylases in cancer epigenetics and therapy. Oncotarget 2018, 28, 34429–34448.
- 35 Lee, M.G.; Wynder, C.; Cooch, N.; Shiekhattar, R. An essential role for CoREST in nucleosomal histone 3 lysine 4 demethyla-tion. Nature 2005, 437, 432–435.
- 36 Ciccone, D.N.; Su, H.; Hevi, S.; Gay, F.; Lei, H.; Bajko, J.; Xu, G.; Li, E.; Chen, T. KDM1B is a histone H3K4 demethylase re-quired to establish maternal genomic imprints. Nature 2009, 461, 415–418.
- 37 Yang, Z.; Jiang, J.; Stewart, M.D.; Qi, S.; Yamane, K.; Li, J.; Zhang, Y.; Wong, J. AOF1 is a histone H3K4 demethylase pos-sessing demethylase activity-independent repression function. Cell Res. 2010, 20, 276–287.
- 38 Yamane, K.; Tateishi, K.; Klose, R.J., Fang, J.; Fabrizio, L.A.; Erdjument-Bromage, H.; Taylor-Papadimitriou, J.; Tempst, P.; Yi Zhang PLU-1 is an H3K4 demethylase involved in transcriptional repression and breast cancer cell proliferation. Mol. Cell 2007, 25, 801–812.
- 39 Christensen, J.; Agger, K.; Cloos, P.A.C.; Pasini, D.; Rose, S.; Sennels, L.; Rappsilber, J.; Hansen, K.H.; Salcini, A.E.; Helin, K.; RBP2 belongs to a family of demethylases, specific for tri- and dimethylated lysine 4 on histone 3. Cell 2007, 128, 1063–1076.
- 40 Iwase, S.; Lan, F.; Bayliss, P.; de la Torre-Ubieta, L.; Huarte, M.; Hank, H.Q.; Whetstine, J.R., Bonni, A.; Roberts, T.M.; Shi, Y. The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell 2007, 128, 1077–1088.
- 41 Klose, R.J.; Yan, Q.; Tothova, Z.; Yamane, K.; Erdjument-Bromage, E.; Tempst, P.; Gilliland, D.G.; Zhang, Y.; Kaelin Jr, W. J. The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell 2007, 128, 889–900.
- 42 Lee, M.G.; Norman, J.; Shilatifard, A.; Shiekhattar, R.; Physical and functional association of a trimethyl H3K4 demethylase and Ring6a/MBLR, a polycomb-like protein. Cell 2007, 128, 877–887.
- 43 Secombe, J.; Li, L.; Carlos, L. and Eisenman, R.N. The Trithorax group protein Lid is a trimethyl histone H3K4 demethylase required for dMyc-induced cell growth. Genes Dev. 2007, 21, 537–551.
- 44 Seward, D.J.; Cubberley, G.; Kim, S.; Schonewald, M.; Zhang, L.; Tripet, B.; Bentley, D.L. Demethylation of trimethylated histone H3 Lys4 in vivo by JARID1 JmjC proteins. Nat. Struct. Mol. Biol. 2007, 14, 240–242.
- 45 Tahiliani, M.; Mei, P.; Fang, R.; et al. The histone H3K4 demethylase SMCX links REST target genes to X- linked mental re-tardation. Nature 2007, 447, 601–605.
- 46 Pasini, D.; Hansen, K.H.; Christensen, J.; Agger, K.; Cloos, P.A. and Helin, K. Coordinated regulation of transcriptional re-pression by the RBP2 H3K4 demethylase and Polycomb-repressive complex 2. Genes Dev. 2008, 22, 1345–1355.
- 47 Vermeulen, M.; Mulder, K.W.; Denissov, S.; Pim Pijnappel, W.W.M.; van Schaik, F.M.A.; Varier, R.A.; Baltissen, M.P.A.; Stunnenberg, H.G.; Mann, M. and Timmers, H.Th.M. Selective Anchoring of TFIID to Nucleosomes by Trimethylation of Histone H3 Lysine 4. Cell 2007, 131, 58–69.
- 48 Zhang, Y.; Qian Li, J.L. Coordinated regulation of retinoic acid signaling pathway by KDM5B and polycomb repressive com-plex 2. J. Cell Biochem. 2014, 115, 1528–1538.
- 49 Nishibuchi, G.; Shibata, Y.; Hayakawa, T.; Hayakawa, N.; Ohtani, Y.; Sinmyozu, K.; Tagami, H.; Nakayama, J. Physical and functional interactions between the histone H3K4 demethylase KDM5A and the nucleosome remodeling and deacetylase (NuRD) complex. J. Biol. Chem. 2014, 289, 28956–28970.
- 50 Li, Q.; Shi, L.; Gui, B.; Yu, W.; Wang, J.; Zhang, D.; Han, X.; Yao, Z.; Shang, Y. Binding of the JmjC demethylase JARID1B to LSD1/NuRD suppresses angiogenesis and metastasis in breast cancer cells by repressing chemokine CCL14. Cancer Res. 2011, 71, 6899–6908.
- 51 Scibetta, A.G.; Santangelo, S.; Coleman, J.; Hall, D.; Chaplin, T.; Copier, J.; Catchpole, S.; Burchell, J.; Taylor-Papadimitriou, J. Functional analysis of the transcription repressor PLU-1/JARID1B. Mol. Cell Biol. 2007, 27, 7220–7235.
- 52 Verrier, L.; Vandromme, M.; Trouche, D. Histone demethylases in chromatin cross-talks. Biol. Cell, 2011, 103, 381–401.
- 53 Barrett, A.; Santangelo, S.; Tan, K.; Catchpole, S.; Roberts, K.; Spencer-Dene, B.; Hall, D.; Scibetta, A.; Burchell, J.; et al. Breast cancer associated transcriptional repressor PLU-1/JARID1B interacts directly with histone deacetylases. Int. J. Cancer 2007, 121, 265–275.
- 54 Lloret-Llinares, M.; Pérez-Lluch, S.; Rossell, D.; Morán, T.; Ponsa-Cobas, J.; Auer, H.; Corominas, M.; Azorín, F. dKDM5/LID regulates H3K4me3 dynamics at the transcription-start site (TSS) of actively transcribed developmental genes. Nucleic Acids Res. 2012, 40, 9493–9505.
- 55 He, R.; Kidder, B.L. H3K4 demethylase KDM5B regulates global dynamics of transcription elongation and alternative splicing in embryonic stem cells. Nucleic Acids Res. 2017, 45, 6427–6441.
- 56 Laurent, B.; Ruitu, L.; Murn, J.; Hempel, K.; Ferrao, R.; Xiang, Y.; Liu, S.; et al. A specific LSD1/KDM1A isoform regulates neuronal differentiation through H3K9 demethylation. Mol. Cell 2015, 57, 957–970.
- 57 Metzger, E.; Wissmann, M.; Yin, N.; Müller, J.M.; Schneider, R.; Peters, A. H. F. M.; Günther, T.; Buettner, R.; Schüle, R. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 2005, 437, 436–439.
- 58 Wang, J.; Scully, K.; Zhu, X.; Cai, L.; Zhang, J.; Prefontaine, G.G.; Krones, A.; Ohgi, K.A.; Zhu, P.; Garcia-Bassets, I.; Liu, F; et al. Opposing LSD1 complexes function in developmental gene activation and repression programmes. Nature 2007, 446, 882–887.
- 59 Perillo, B.; Ombra, M.N.; Bertoni, A.; Cuozzo, C.; Sacchetti, S.; Sasso, A.; Chiariotti, L.; Malorni, A.; Abbondanza, C.; Avvedimento, E.V. DNA oxidation as triggered by H3K9me2 demethylation drives estrogen-induced gene expression. Science 2008, 319, 202–206.
- 60 Cai, C.M.; He, H.H.; Gao, S.; Chen, S.; Yu, Z.; Gao, Y.; Chen, S.; Chen, M.W.; et al. Lysine-specific demethylase 1 has dual func- tions as a major regulator of androgen receptor transcriptional activity. Cell Rep. 2014, 9, 1618–1627.
- 61 Wang, J.; Telese, F.; Tan, Y.; Li, W.; Jin, C.; He, X.; et al. LSD1n is an H4K20 demethylase regulat- ing memory formation via transcriptional elongation control. Nat. Neurosci. 2015, 18, 1256–1264.
- 62 Garcia-Bassets, I.; Kwon, Y.S.; Telese, F.; Prefontaine, G.G.; Hutt, K.R.; Cheng, C.S.; Ju, B.G.; Ohgi, K.A.; Wang, J.; Es-coubet-Lozach, L.; et al. Histone methylation-dependent mechanisms impose ligand dependency for gene activation by nu-clear receptors. Cell 2007, 128, 505–518.
- 63 Saleque, S.; Kim, J.W.; Rooke, H.M.; Orkin, S.H. Epigenetic regulation of hematopoietic differentiation by Gfi-1 and Gfi-1b is mediated by the cofactors CoREST and LSD1. Mol. Cell 2007, 27, 562–572.
- 64 Maiques-Diaz, A.; Spencer, G.J.; Lynch, J.T.; Ciceri, F.; Williams, E.L.; Amaral, F.M.R.; et al. Enhancer activation by pharma-co- logic displacement of LSD1 from GFI1 induces differentiation in acute myeloid leukemia. Cell Rep. 2018, 22, 3641–3659.
- 65 Majello, B.; Gorini, F.; Sacca, C.D.; Amente, S. Expanding the role of the histone lysine-specific demethylase LSD1 in cancer. Cancers 2019, 11, 324.
- 66 Huang, J.; Sengupta, H.; Espejo, A.B.; Lee, M.G.; Dorsey, J.A.; et al. p53 is regulated by the lysine demethylase LSD1. Nature 2007, 449, 105–108.
- 67 Cho, H.S.; Suzuki, T.; Dohmae, N.; Hayami, S.; Unoki, M.; Yoshimatsu, M.; Toyokawa, G.; et al. Demethylation of RB regu-lator MYPT1 by histone demethylase LSD1 promotes cell cycle progression in cancer cells. Cancer Res. 2011, 71, 655–660.
- 68 Kontaki, H.; Talianidis, I. Lysine methylation regulates E2F1- induced cell death. Mol. Cell 2010, 39, 152–160.
- 69 Baek, S.H.; Kim, K.I. Regulation of HIF-1 alpha stability by lysine methylation. BMB Rep. 2016, 49, 245–246.
- 70 Lan, F.; Nottke, A.C.; Shi, Y. Mechanisms involved in the regulation of histone lysine demethylases. Curr. Opin. Cell Biol. 2008, 20, 316–325.
- 71 Ambrosio, S.; Sacca, C.D.; Majello, B. Epigenetic regulation of epithelial to mesenchymal transition by the Lysine-specific. demethylase LSD1/KDM1A. Biochim. Biophys. Acta Gene Regul. Mech. 2017, 1860, 905–910.
- 72 Whyte, W.A.; Bilodeau, S.; Orlando, D.A.; Hoke, H.A.; Frampton, G.M.; et al. Enhancer decommissioning by LSD1 during embryonic stem cell differentiation. Nature 2012, 482, 221–225.
- 73 Amente, S.; Lania, L.; Majello, B. The histone LSD1 demethylase in stemness and cancer transcription programs. Biochim. Biophys. Acta 2013, 1829, 981–986.
- Please check and comment entries here.