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Structure, Activity and Function of the MLL2 (KMT2B) Protein Lysine Methyltransferase

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Structure, Activity and Function of the MLL2 (KMT2B) Protein Lysine Methyltransferase life Review Structure, Activity and Function of the MLL2 (KMT2B) Protein Lysine Methyltransferase Alexia Klonou 1, Sarantis Chlamydas 1,2 and Christina Piperi 1,* 1 Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; [email protected] (A.K.); [email protected] (S.C.) 2 Research and Development Department, Active Motif, Inc., Carlsbad, CA 92008, USA * Correspondence: [email protected]; Tel.: +30-210-7462610 Abstract: The Mixed Lineage Leukemia 2 (MLL2) protein, also known as KMT2B, belongs to the fam- ily of mammalian histone H3 lysine 4 (H3K4) methyltransferases. It is a large protein of 2715 amino acids, widely expressed in adult human tissues and a paralog of the MLL1 protein. MLL2 contains a characteristic C-terminal SET domain responsible for methyltransferase activity and forms a protein complex with WRAD (WDR5, RbBP5, ASH2L and DPY30), host cell factors 1/2 (HCF 1/2) and Menin. The MLL2 complex is responsible for H3K4 trimethylation (H3K4me3) on specific gene promoters and nearby cis-regulatory sites, regulating bivalent developmental genes as well as stem cell and germinal cell differentiation gene sets. Moreover, MLL2 plays a critical role in development and germ line deletions of Mll2 have been associated with early growth retardation, neural tube defects and apoptosis that leads to embryonic death. It has also been involved in the control of voluntary movement and the pathogenesis of early stage childhood dystonia. Additionally, tumor-promoting functions of MLL2 have been detected in several cancer types, including colorectal, hepatocellu- lar, follicular cancer and gliomas. In this review, we discuss the main structural and functional Citation: Klonou, A.; Chlamydas, S.; aspects of the MLL2 methyltransferase with particular emphasis on transcriptional mechanisms, Piperi, C. Structure, Activity and gene regulation and association with diseases. Function of the MLL2 (KMT2B) Protein Lysine Methyltransferase. Life Keywords: MLL2; structure; H3K4me3; chromatin regulation; disease; dystonia; cancer 2021, 11, 823. https://doi.org/ 10.3390/life11080823 Academic Editors: Albert Jeltsch and 1. Introduction Arunkumar Dhayalan Chromatin remodeling is a key feature of gene regulation and activity, with histone modifications playing a primary role in the modulation of the chromatin landscape and Received: 8 July 2021 gene expression. Among the most prominent histone modifications is the methylation of Accepted: 10 August 2021 Published: 12 August 2021 histone 3 (H3) lysine (K) residues, detected on gene enhancers and specific gene promoter regions. Mono- and di-methylation of H3K4 (H3K4me1/me2) is mainly observed in Publisher’s Note: MDPI stays neutral enhancers whereas H3K4me3 is present on active gene promoters. Several protein lysine with regard to jurisdictional claims in methyltransferases (PKMTs), including Mixed Lineage Leukemia 1-5 (MLL1-5/KMT2A-E), published maps and institutional affil- SET Domain-Containing 7 (SET7), SET and MYND Domain-Containing 3 (SMYD3), SET9 iations. and PR/SET Domain 9 (PRDM9), are responsible for the transfer of methyl groups onto H3K4. The largest group of human lysine 4 (K4) HMKTs is the Mixed Lineage Leukemia (MLL/KMT2) protein family, named after the association with a subset of incurable acute leukemias of its founding member. All family members are characterized by a highly conserved catalytically active Su(var)3-9, Enhancer of zeste and Trithorax (SET) domain [1]. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. In yeast, there is a single MLL homolog comprised of a SET domain (SET1) which cat- This article is an open access article alyzes mono-, di- and tri-methylation of histone H3K4, whereas in Drosophila melanogaster distributed under the terms and there are three homologs, namely, Set1, Trithorax-related (Trr) and Trithorax (Trx), respon- conditions of the Creative Commons sible for H3K4 methyltransferase activity [2]. The Trithorax group of proteins has been Attribution (CC BY) license (https:// identified as regulators of Homeotic (Homeobox) genes in Drosophila and are essential for creativecommons.org/licenses/by/ body patterning in multicellular organisms. Their activity is antagonized by the Polycomb 4.0/). group of proteins (PcP) which exerts the repressive role in Homeobox genes expression. Life 2021, 11, 823. https://doi.org/10.3390/life11080823 https://www.mdpi.com/journal/life Life 2021, 11, x FOR PEER REVIEW 2 of 14 been identified as regulators of Homeotic (Homeobox) genes in Drosophila and are essen- tial for body patterning in multicellular organisms. Their activity is antagonized by the Polycomb group of proteins (PcP) which exerts the repressive role in Homeobox genes Life 2021, 11, 823 expression. 2 of 14 Mammalian cells possess six SET1-like H3K4 methyltransferases, including the four MLL1-4 family proteins and Set1A and Set1B (KMT2F, KMT2G). Sequence homology has shownMammalian that two cells human possess homologs six SET1-like exist for H3K4 each methyltransferases,of the H3K4 methyltransferase including the proteins four MLL1-4in Drosophila family. proteinsMore specifically, and Set1A MLL1/KMT2A and Set1B (KMT2F, and MLL2 KMT2G). (4)/KMT2B Sequence have homology a similar has do- shownmain thatstructure two human to Trx, homologs MLL3/KMT2C exist for and each MLL4 of the(2)/KMT2D H3K4 methyltransferase are homologous proteins to Trr while in DrosophilaSET1A and. More SET1B specifically, are homologous MLL1/KMT2A to Set1/dSe and MLL2t1 [2]. (4)/KMT2BAlthough MLL5 have (KMT2E) a similar domainwas orig- structureinally considered to Trx, MLL3/KMT2C as an MLL and family MLL4 member, (2)/KMT2D its divergent are homologous SET domain to Trr whilefrom the SET1A other andfamily SET1B members are homologous as well as tothe Set1/dSet1 lack of lysine [2]. methyltransferase Although MLL5 (KMT2E) activity, have was originallyre-classified consideredit to a different as an subgroup MLL family of SET member, domain its divergentproteins. SET domain from the other family membersOf asimportance, well as the the lack MLL of lysine family methyltransferase members deposit activity, distinct have H3K4 re-classified methylation it tostates a differentand target subgroup different of SETgenomic domain regions. proteins. SET1A/B enzymes establish global H3K4me3 levels throughOf importance, a crosstalk the with MLL the family monoubiquitinati members depositon of the distinct H2B process, H3K4 methylation whereas MLL1 states and andMLL2 target catalyze different the genomic H3K4me3 regions. modifications SET1A/B at enzymes specific gene establish promoters. global H3K4me3 MLL2 further levels im- throughplements a crosstalk H3K4me3 with at thebivalently monoubiquitination marked gene ofpromoters, the H2B process,while MLL3/4 whereas enzymes MLL1 andmedi- MLL2ate H3K4me1 catalyze theat transcription H3K4me3 modifications enhancers throughout at specific the gene human promoters. genome MLL2[3,4]. further implementsAlthough H3K4me3 a direct at functional bivalently role marked of H3K4 gene in transcription promoters, while is still MLL3/4 under investigation, enzymes mediatethe aberrant H3K4me1 transcription at transcription mediated enhancers by MLL throughout family members the human has a genome significant [3,4 ].impact in geneAlthough regulation a direct and normal functional cell rolephysiology of H3K4 with in transcription an ultimate connection is still under to investigation,developmental thedisorders aberrant and transcription cancer [5]. mediated by MLL family members has a significant impact in gene regulationHerein, we and discuss normal the cell major physiology structural with an and ultimatebiochemical connection characteristics to developmental of the MLL2 disorders(KMT2B) and methyltransferase cancer [5]. with emphasis on its cellular and molecular functions as well as Herein,its connection we discuss to diseases. the major structural and biochemical characteristics of the MLL2 (KMT2B) methyltransferase with emphasis on its cellular and molecular functions as well as2. its The connection MLL2 Protein to diseases. Genome duplication during mammalian evolution resulted in two paralogs in each 2. The MLL2 Protein MLL subgroup (MLL1/KMT2A and MLL2(4)/KMT2B) which are analogous proteins withinGenome the Trx-related duplication subgroup, during mammalian referred to evolutionas the MLX resulted family in(MLL-TRX) two paralogs [6]. in each MLL subgroupThe MLL2 (MLL1/KMT2A (KMT2B) gene (OMIM and MLL2(4)/KMT2B) 606834) is located which on chromosome are analogous 19q13.12 proteins and withinconsists the of Trx-related an 8.5–9 kb subgroup, transcript, referred spanning to as 20 the kbMLX of genomic family DNA. (MLL-TRX) It is expressed [6]. in most humanThe MLL2 tissues (KMT2B) [7] and hasgene a similar (OMIM genomic 606834) structure is located with on MLL1 chromosome, present 19q13.12in chromosome and consists11q23. of an 8.5–9 kb transcript, spanning 20 kb of genomic DNA. It is expressed in most MLL1 humanThe tissues MLL2 [7] protein and has is a2715 similar amino genomic acids in structure length and with its structural, present organization in chromo- in- some 11q23. cludes the catalytically active C-terminal SET domain, an AT hook, a CXXC domain and The MLL2 protein is 2715 amino acids in length and its structural organization in- several plant homeotic domains (PHD) in the N-terminal region (Figure 1) [6,8]. The SET cludes the catalytically active C-terminal SET domain, an AT
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