Skip to main content

Advertisement

Log in

MLL5 (KMT2E): structure, function, and clinical relevance

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

The mixed lineage leukemia (MLL) family of genes, also known as the lysine N-methyltransferase 2 (KMT2) family, are homologous to the evolutionarily conserved trithorax group that plays critical roles in the regulation of homeotic gene (HOX) expression and embryonic development. MLL5, assigned as KMT2E on the basis of its SET domain homology, was initially categorized under MLL (KMT2) family together with other six SET methyltransferase domain proteins (KMT2A–2D and 2F–2G). However, emerging evidence suggests that MLL5 is distinct from the other MLL (KMT2) family members, and the protein it encodes appears to lack intrinsic histone methyltransferase (HMT) activity towards histone substrates. MLL5 has been reported to play key roles in diverse biological processes, including cell cycle progression, genomic stability maintenance, adult hematopoiesis, and spermatogenesis. Recent studies of MLL5 variants and isoforms and putative MLL5 homologs in other species have enriched our understanding of the role of MLL5 in gene expression regulation, although the mechanism of action and physiological function of MLL5 remains poorly understood. In this review, we summarize recent research characterizing the structural features and biological roles of MLL5, and we highlight the potential implications of MLL5 dysfunction in human disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Emerling BM, Bonifas J, Kratz CP, Donovan S, Taylor BR, Green ED, Le Beau MM, Shannon KM (2002) MLL5, a homolog of Drosophila trithorax located within a segment of chromosome band 7q22 implicated in myeloid leukemia. Oncogene 21(31):4849–4854

    Article  CAS  PubMed  Google Scholar 

  2. Kratz CP, Emerling BM, Donovan S, Laig-Webster M, Taylor BR, Thompson P, Jensen S, Banerjee A, Bonifas J, Makalowski W (2001) Candidate gene isolation and comparative analysis of a commonly deleted segment of 7q22 implicated in myeloid malignancies. Genomics 77(3):171–180

    Article  CAS  PubMed  Google Scholar 

  3. Madan V, Madan B, Brykczynska U, Zilbermann F, Hogeveen K, Döhner K, Döhner H, Weber O, Blum C, Rodewald HR, Sassone-Corsi P, Peters AH, Fehling HJ (2009) Impaired function of primitive hematopoietic cells in mice lacking the Mixed-Lineage-Leukemia homolog MLL5. Blood 113(7):1444–1454

    Article  CAS  PubMed  Google Scholar 

  4. Deng L-W, Chiu I, Strominger JL (2004) MLL 5 protein forms intranuclear foci, and overexpression inhibits cell cycle progression. Proc Natl Acad Sci USA 101(3):757–762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mas-y-Mas S, Barbon M, Teyssier C, Déméné H, Carvalho JE, Bird LE, Lebedev A, Fattori J, Schubert M, Dumas C, Bourguet W, le Maire A (2016) The human mixed lineage leukemia 5 (MLL5), a sequentially and structurally divergent SET domain-containing protein with no intrinsic catalytic activity. PLos One 11(11):e0165139

    Article  PubMed  PubMed Central  Google Scholar 

  6. Sun X-J, Xu P-F, Zhou T, Hu M, Fu C-T, Zhang Y, Jin Y, Chen Y, Chen S-J, Huang Q-H, Liu TX, Chen Z (2008) Genome-wide survey and developmental expression mapping of zebrafish SET domain-containing genes. PLoS One 3(1):e1499

    Article  PubMed  PubMed Central  Google Scholar 

  7. Glaser S, Schaft J, Lubitz S, Vintersten K, van der Hoeven F, Tufteland KR, Aasland R, Anastassiadis K, Ang S-L, Stewart AF (2006) Multiple epigenetic maintenance factors implicated by the loss of Mll2 in mouse development. Development 133(8):1423–1432

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. Pijnappel WP, Schaft D, Roguev A, Shevchenko A, Tekotte H, Wilm M, Rigaut G, Séraphin B, Aasland R, Stewart AF (2001) The S. cerevisiae SET3 complex includes two histone deacetylases, Hos2 and Hst1, and is a meiotic-specific repressor of the sporulation gene program. Genes Dev 15(22):2991–3004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Del Rizzo PA, Trievel RC (2011) Substrate and product specificities of SET domain methyltransferases. Epigenetics 6(9):1059–1067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dillon SC, Zhang X, Trievel RC, Cheng X (2005) The SET-domain protein superfamily: protein lysine methyltransferases. Genome Biol 6(8):227

    Article  PubMed  PubMed Central  Google Scholar 

  12. Li Y, Han J, Zhang Y, Cao F, Liu Z, Li S, Wu J, Hu C, Wang Y, Shuai J, Chen J, Cao L, Li D, Shi P, Tian C, Zhang J, Dou Y, Li G, Chen Y, Lei M (2016) Structural basis for activity regulation of MLL family methyltransferases. Nature 530(7591):447–452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sebastian S, Sreenivas P, Sambasivan R, Cheedipudi S, Kandalla P, Pavlath GK, Dhawan J (2009) MLL5, a trithorax homolog, indirectly regulates H3K4 methylation, represses cyclin A2 expression, and promotes myogenic differentiation. Proc Natl Acad Sci USA 106(12):4719–4724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wu M, Wang PF, Lee JS, Martin-Brown S, Florens L, Washburn M, Shilatifard A (2008) Molecular regulation of H3K4 trimethylation by Wdr82, a component of human Set1/COMPASS. Mol Cell Biol 28(24):7337–7344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhou P, Wang Z, Yuan X, Zhou C, Liu L, Wan X, Zhang F, Ding X, Wang C, Xiong S, Wang Z, Yuan J, Li Q, Zhang Y (2013) Mixed lineage leukemia 5 (MLL5) protein regulates cell cycle progression and E2F1-responsive gene expression via association with host cell factor-1 (HCF-1). J Biol Chem 288(24):17532–17543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rincon-Arano H, Halow J, Delrow JJ, Parkhurst SM, Groudine M (2012) UpSET recruits HDAC complexes and restricts chromatin accessibility and acetylation at promoter regions. Cell 151(6):1214–1228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Musselman CA, Kutateladze TG (2009) PHD fingers: epigenetic effectors and potential drug targets. Mol Interventions 9(6):314

    Article  CAS  Google Scholar 

  18. Ali M, Rincón-Arano H, Zhao W, Rothbart SB, Tong Q, Parkhurst SM, Strahl BD, Deng L-W, Groudine M, Kutateladze TG (2013) Molecular basis for chromatin binding and regulation of MLL5. Proc Natl Acad Sci USA 110(28):11296–11301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lemak A, Yee A, Wu H, Yap D, Zeng H, Dombrovski L, Houliston S, Aparicio S, Arrowsmith CH (2013) Solution NMR structure and histone binding of the PHD domain of human MLL5. PLoS One 8(10):e77020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kim T, Buratowski S (2009) Dimethylation of H3K4 by Set1 recruits the Set3 histone deacetylase complex to 5′ transcribed regions. Cell 137(2):259–272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kittler R, Pelletier L, Heninger A-K, Slabicki M, Theis M, Miroslaw L, Poser I, Lawo S, Grabner H, Kozak K, Wagner J, Surendranath V, Richter C, Bowen W, Jackson AL, Habermann B, Hyman AA, Buchholz F (2007) Genome-scale RNAi profiling of cell division in human tissue culture cells. Nat Cell Biol 9(12):1401–1412

    Article  CAS  PubMed  Google Scholar 

  22. Osipovich AB, Gangula R, Vianna PG, Magnuson MA (2016) Setd5 is essential for mammalian development and co-transcriptional regulation of histone acetylation. Development 143 (24):4595–4607

    Article  CAS  PubMed  Google Scholar 

  23. Fujiki R, Chikanishi T, Hashiba W, Ito H, Takada I, Roeder RG, Kitagawa H, Kato S (2009) GlcNAcylation of a histone methyltransferase in retinoic-acid-induced granulopoiesis. Nature 459(7245):455–459

    Article  CAS  PubMed  Google Scholar 

  24. Ding X, Jiang W, Zhou P, Liu L, Wan X, Yuan X, Wang X, Chen M, Chen J, Yang J, Kong C, Li B, Peng C, Wong CC, Hou F, Zhang Y (2015) Mixed lineage leukemia 5 (MLL5) protein stability is cooperatively regulated by O-GlcNac transferase (OGT) and ubiquitin specific protease 7 (USP7). PLoS One 10(12):e0145023

    Article  PubMed  PubMed Central  Google Scholar 

  25. Yew CW, Lee P, Chan WK, Lim VKJ, Tay SK, Tan TM, Deng L-W (2011) A novel MLL5 isoform that is essential to activate E6 and E7 transcription in HPV16/18-associated cervical cancers. Cancer Res 71(21):6696–6707

    Article  CAS  PubMed  Google Scholar 

  26. Nin DS, Huang W, Ali M, Yew CW, Kutateladze TG, Deng L-W (2015) O-GlcNAcylation of MLL5β is essential for MLL5β–AP-1 transcription complex assembly at the HPV16/18-long control region. J Mol Cell Biol 7(2):180–183

    Article  PubMed  PubMed Central  Google Scholar 

  27. Nin DS, Yew CW, Tay SK, Deng L-W (2014) Targeted silencing of MLL5β inhibits tumor growth and promotes gamma-irradiation sensitization in HPV16/18-associated cervical cancers. Mol Cancer Ther 13(11):2572–2582

    Article  CAS  PubMed  Google Scholar 

  28. Sennepin A, Baychelier F, Guihot A, Nel I, Fang RHT, Calin R, Katlama C, Simon A, Crouzet J, Debré P, Vieillard V (2013) NKp44L expression on CD4 + T cells is associated with impaired immunological recovery in HIV-infected patients under highly active antiretroviral therapy. Aids 27(12):1857–1866

    Article  CAS  PubMed  Google Scholar 

  29. Baychelier F, Sennepin A, Ermonval M, Dorgham K, Debré P, Vieillard V (2013) Identification of a cellular ligand for the natural cytotoxicity receptor NKp44. Blood 122(17):2935–2942

    Article  CAS  PubMed  Google Scholar 

  30. Rajagopalan S, Long EO (2013) Found: a cellular activating ligand for NKp44. Blood 122(17):2921–2922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Vieillard V, Baychelier F, Debré P (2014) NKp44L: a new tool for fighting cancer. Oncoimmunology 3(3):e27988

    Article  PubMed  PubMed Central  Google Scholar 

  32. Vieillard V, Strominger JL, Debré P (2005) NK cytotoxicity against CD4 + T cells during HIV-1 infection: a gp41 peptide induces the expression of an NKp44 ligand. Proc Natl Acad Sci USA 102(31):10981–10986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cheng F, Liu J, Zhou SH, Wang XN, Chew JF, Deng L-W (2008) RNA interference against mixed lineage leukemia 5 resulted in cell cycle arrest. Int J Biochem Cell Biol 40(11):2472–2481

    Article  CAS  PubMed  Google Scholar 

  34. Cheng F, Liu J, Teh C, Chong S, Korzh V, Jiang Y, Deng L (2011) Camptothecin-induced downregulation of MLL5 contributes to the activation of tumor suppressor p53. Oncogene 30(33):3599–3611

    Article  CAS  PubMed  Google Scholar 

  35. Liu J, Wang XN, Cheng F, Liou Y-C, Deng L-W (2010) Phosphorylation of mixed lineage leukemia 5 by CDC2 affects its cellular distribution and is required for mitotic entry. J Biol Chem 285(27):20904–20914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rentas S, Saberianfar R, Grewal C, Kanippayoor R, Mishra M, McCollum D, Karagiannis J (2012) The SET domain protein, Set3p, promotes the reliable execution of cytokinesis in Schizosaccharomyces pombe. PLoS One 7(2):e31224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Liu J, Cheng F, Deng L-W (2012) MLL5 maintains genomic integrity by regulating the stability of the chromosomal passenger complex through a functional interaction with Borealin. J Cell Sci 125(19):4676–4685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhao W, Liu J, Zhang X, Deng L-W (2016) MLL5 maintains spindle bipolarity by preventing aberrant cytosolic aggregation of PLK1. J Cell Biol 212(7):829–843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhang Y, Wong J, Klinger M, Tran MT, Shannon KM, Killeen N (2009) MLL5 contributes to hematopoietic stem cell fitness and homeostasis. Blood 113(7):1455–1463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Heuser M, Yap DB, Leung M, de Algara TR, Tafech A, McKinney S, Dixon J, Thresher R, Colledge B, Carlton M, Humphries RK, Aparicio SA (2009) Loss of MLL5 results in pleiotropic hematopoietic defects, reduced neutrophil immune function, and extreme sensitivity to DNA demethylation. Blood 113(7):1432–1443

    Article  CAS  PubMed  Google Scholar 

  41. Liu H, Westergard TD, Hsieh JJ-D (2009) MLL5 governs hematopoiesis: a step closer. Blood 113(7):1395–1396

    Article  CAS  PubMed  Google Scholar 

  42. Tasdogan A, Kumar S, Allies G, Bausinger J, Beckel F, Hofemeister H, Mulaw M, Madan V, Scharfetter-Kochanek K, Feuring-Buske M, Doehner K, Speit G, Stewart AF, Fehling HJ (2016) DNA damage-induced HSPC malfunction depends on ROS accumulation downstream of IFN-1 signaling and bid mobilization. Cell Stem Cell 19(6):752–767

    Article  CAS  PubMed  Google Scholar 

  43. Yap DB, Walker DC, Prentice LM, McKinney S, Turashvili G, Mooslehner-Allen K, de Algara TR, Fee J, de Tassigny XdA, Colledge WH, Aparicio S (2011) Mll5 is required for normal spermatogenesis. PLoS One 6(11):e27127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wong JC, Zhang Y, Lieuw KH, Tran MT, Forgo E, Weinfurtner K, Alzamora P, Kogan SC, Akagi K, Wolff L, Le Beau MM, Killeen N, Shannon K (2010) Use of chromosome engineering to model a segmental deletion of chromosome band 7q22 found in myeloid malignancies. Blood 115(22):4524–4532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Damm F, Oberacker T, Thol F, Surdziel E, Wagner K, Chaturvedi A, Morgan M, Bomm K, Göhring G, Lübbert M, Kanz L, Fiedler W, Schlegelberger B, Heil G, Schlenk RF, Döhner K, Döhner H, Krauter J, Ganser A, Heuser M (2011) Prognostic importance of histone methyltransferase MLL5 expression in acute myeloid leukemia. J Clin Oncol 29(6):682–689

    Article  CAS  PubMed  Google Scholar 

  46. Yun H, Damm F, Yap D, Schwarzer A, Chaturvedi A, Jyotsana N, Lübbert M, Bullinger L, Döhner K, Geffers R, Aparicio S, Humphries RK, Ganser A, Heuser M (2014) Impact of MLL5 expression on decitabine efficacy and DNA methylation in acute myeloid leukemia. Haematologica 99(9):1456–1464

    Article  PubMed  PubMed Central  Google Scholar 

  47. Milne TA (2014) MLL5 expression as a biomarker for DNA hypermethylation and sensitivity to epigenetic therapy. Haematologica 99(9):1405–1407

    Article  PubMed  PubMed Central  Google Scholar 

  48. Lucena-Araujo AR, Kim HT, Jacomo RH, Melo RA, Bittencourt R, Pasquini R, Pagnano K, Fagundes EM, Chauffaille M, Chiattone CS, Lima AS, Kwaan HC, Gallagher R, Niemeyer CM, Schrier SL, Tallman MS, Grimwade D, Ganser A, Berliner N, Ribeiro RC, Lo-Coco F, Löwenberg B, Sanz MA, Rego EM (2014) Prognostic impact of KMT2E transcript levels on outcome of patients with acute promyelocytic leukaemia treated with all-trans retinoic acid and anthracycline-based chemotherapy: an International Consortium on Acute Promyelocytic Leukaemia study. Br J Haematol 166(4):540–549

    Article  CAS  PubMed  Google Scholar 

  49. Forbes SA, Beare D, Gunasekaran P, Leung K, Bindal N, Boutselakis H, Ding M, Bamford S, Cole C, Ward S, Kok CY, Jia M, De T, Teague JW, Stratton MR, McDermott U, Campbell PJ (2015) COSMIC: exploring the world’s knowledge of somatic mutations in human cancer. Nucleic Acids Res 43(D1):D805–D811

    Article  PubMed  Google Scholar 

  50. Rabello DdA, De Moura CA, De Andrade RV, Motoyama AB, Silva FP (2013) Altered expression of MLL methyltransferase family genes in breast cancer. Int J Oncol 43(2):653–660

    Google Scholar 

  51. Hodge JC, Park PJ, Dreyfuss JM, Assil-Kishawi I, Somasundaram P, Semere LG, Quade BJ, Lynch AM, Stewart EA, Morton CC (2009) Identifying the molecular signature of the interstitial deletion 7q subgroup of uterine leiomyomata using a paired analysis. Genes Chromosom Cancer 48(10):865–885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Dal Cin P, Van Den Berghe H, Sciot R, De Wever I (1997) Deletion of the long arm of chromosome 7 in lipoma. Cancer Genet Cytogenet 96(1):85–86

    Article  CAS  PubMed  Google Scholar 

  53. Dal Cin P, Vanni R, Marras S, Moerman P, Kools P, Andria M, Valdes E, Deprest J, Van de Ven W, Van Den Berghe H (1995) Four cytogenetic subgroups can be identified in endometrial polyps. Cancer Res 55(7):1565–1568

    CAS  PubMed  Google Scholar 

  54. Gallo M, Coutinho FJ, Vanner RJ, Gayden T, Mack SC, Murison A, Remke M, Li R, Takayama N, Desai K, Lee L, Lan X, Park NI, Barsyte-Lovejoy D, Smil D, Sturm D, Kushida MM, Head R, Cusimano MD, Bernstein M, Clarke ID, Dick JE, Pfister SM, Rich JN, Arrowsmith CH, Taylor MD, Jabado N, Bazett-Jones DP, Lupien M, Dirks PB (2015) MLL5 orchestrates a cancer self-renewal state by repressing the histone variant H3. 3 and globally reorganizing chromatin. Cancer Cell 28(6):715–729

    Article  CAS  PubMed  Google Scholar 

  55. Dong S, Walker MF, Carriero NJ, DiCola M, Willsey AJ, Adam YY, Waqar Z, Gonzalez LE, Overton JD, Frahm S, Keaney JF 3rd, Teran NA, Dea J, Mandell JD, Hus Bal V, Sullivan CA, DiLullo NM, Khalil RO, Gockley J, Yuksel Z, Sertel SM, Ercan-Sencicek AG, Gupta AR, Mane SM, Sheldon M, Brooks AI, Roeder K, Devlin B, State MW, Wei L, Sanders SJ (2014) De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder. Cell Reports 9(1):16–23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Uliana V, Grosso S, Cioni M, Ariani F, Papa FT, Tamburello S, Rossi E, Katzaki E, Mucciolo M, Marozza A, Pollazzon M, Mencarelli MA, Mari F, Balestri P, Renieri A (2010) 3.2 Mb microdeletion in chromosome 7 bands q22. 2–q22. 3 associated with overgrowth and delayed bone age. Eur J Med Genet 53(3):168–170

    Article  PubMed  Google Scholar 

  57. Jensen LR, Amende M, Gurok U, Moser B, Gimmel V, Tzschach A, Janecke AR, Tariverdian G, Chelly J, Fryns J-P, Van Esch H, Kleefstra T, Hamel B, Moraine C, Gecz J, Turner G, Reinhardt R, Kalscheuer VM, Ropers HH, Lenzner S (2005) Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation. Am J Hum Genet 76(2):227–236

    Article  CAS  PubMed  Google Scholar 

  58. Björkegren JL, Hägg S, Talukdar HA, Asl HF, Jain RK, Cedergren C, Shang M-M, Rossignoli A, Takolander R, Melander O, Hamsten A, Michoel T, Skogsberg J (2014) Plasma cholesterol–induced lesion networks activated before regression of early, mature, and advanced atherosclerosis. PLoS Genet 10(2):e1004201

    Article  PubMed  PubMed Central  Google Scholar 

  59. Yuan Q, Xie X, Fu Z, Ma X, Yang Y, Huang D, Liu F, Dai C, Ma Y (2014) Association of the histone-lysine N-methyltransferase MLL5 gene with coronary artery disease in Chinese Han people. Meta Gene 2:514–524

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work is supported by the Ministry of Education Academic Research Fund Tier 1 Grant (R-183-000-337-112) and Tier 2 Grant (R-183-000-354-112), Singapore. We thank K. McLaughlin of Insight Editing London for critical review of the manuscript. We also thank Z.W. Lee and W. Zhao for helpful suggestions regarding manuscript structure.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lih-Wen Deng.

Ethics declarations

Conflict of interest

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, X., Novera, W., Zhang, Y. et al. MLL5 (KMT2E): structure, function, and clinical relevance. Cell. Mol. Life Sci. 74, 2333–2344 (2017). https://doi.org/10.1007/s00018-017-2470-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-017-2470-8

Keywords

Navigation