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• W2024584416 abstract "Cells employ elaborate mechanisms to introduce structural and chemical variation into chromatin. Here, we focus on one such element of variation: methylation of lysine 4 in histone H3 (H3K4). We assess a growing body of literature, including treatment of how the mark is established, the patterns of methylation, and the functional consequences of this epigenetic signature. We discuss structural aspects of the H3K4 methyl recognition by the downstream effectors and propose a distinction between sequence-specific recruitment mechanisms and stabilization on chromatin through methyl-lysine recognition. Finally, we hypothesize how the unique properties of the polyvalent chromatin fiber and associated effectors may amplify small differences in methyl-lysine recognition, simultaneously allowing for a dynamic chromatin architecture. Cells employ elaborate mechanisms to introduce structural and chemical variation into chromatin. Here, we focus on one such element of variation: methylation of lysine 4 in histone H3 (H3K4). We assess a growing body of literature, including treatment of how the mark is established, the patterns of methylation, and the functional consequences of this epigenetic signature. We discuss structural aspects of the H3K4 methyl recognition by the downstream effectors and propose a distinction between sequence-specific recruitment mechanisms and stabilization on chromatin through methyl-lysine recognition. Finally, we hypothesize how the unique properties of the polyvalent chromatin fiber and associated effectors may amplify small differences in methyl-lysine recognition, simultaneously allowing for a dynamic chromatin architecture. Chromatin is thought to be a master regulator of access to the underlying genome, influencing potentially all DNA-templated processes. Establishment and propagation of gene expression patterns involves proteins, often in complexes, that modify chromatin through the covalent modification of histones and associated DNA. Transmission of chromatin architecture to daughter cells during somatic cell division is thought to be the basis for epigenetics-heritable cell characteristics that are not encoded in the Watson-Crick base pairing of DNA. It remains an intriguing possibility that the identity of a given cell—i.e., what makes a stem cell a stem cell or a neuron a neuron—is owed in large part to potentially heritable chromatin states that dictate the transcriptional status of underlying DNA. Here, we review the current understanding of one epigenetic signature generally associated with transcriptionally active genes: methylated lysine 4 in histone H3 (H3K4), with emphasis on its regulatory functions in vertebrate organisms. We use this single epigenetic mark to illustrate the enormous complexity of (1) enzymatic activities responsible for writing the covalent language, (2) methyltransferase recruitment and regulation mechanisms, and (3) downstream effectors that read the covalent signals to bring about distinct chromatin states. Not discussed is additional regulation provided by the recently discovered new classes of enzymes dedicated to the removal (erasure) of H3K4 methyl marks (see accompanying review by Shi and Whetstine, 2006Shi Y. Whetstine J.R. Dynamic regulation of histone methylation by demethylases.Mol. Cell. 2007; 25 (this issue): 1-14Abstract Full Text Full Text PDF PubMed Scopus (482) Google Scholar [this issue of Molecular Cell]). H3K4 methylation was first discovered in the trout testes (Honda et al., 1975Honda B.M. Dixon G.H. Candido E.P. Sites of in vivo histone methylation in developing trout testis.J. Biol. Chem. 1975; 250: 8681-8685Abstract Full Text PDF PubMed Google Scholar). In subsequent studies, methylation of H3K4 has been linked to transcriptional activation in a variety of eukaryotic species (for recent reviews, see Martin and Zhang, 2005Martin C. Zhang Y. The diverse functions of histone lysine methylation.Nat. Rev. Mol. Cell Biol. 2005; 6: 838-849Crossref PubMed Scopus (1419) Google Scholar and Dehe and Geli, 2006Dehe P.M. Geli V. The multiple faces of Set1.Biochem. Cell Biol. 2006; 84: 536-548Crossref PubMed Google Scholar). Adding to the complexity of epigenetic regulation, lysine residues can be mono-, di-, or trimethylated at the ζ-amine in vivo. Recent genomic-scale analyses of histone modifications allow for general correlations between different H3K4 methylation states, their genomic loci, and gene expression levels (Santos-Rosa et al., 2002Santos-Rosa H. Schneider R. Bannister A.J. Sherriff J. Bernstein B.E. Emre N.C. Schreiber S.L. Mellor J. Kouzarides T. Active genes are tri-methylated at K4 of histone H3.Nature. 2002; 419: 407-411Crossref PubMed Scopus (1431) Google Scholar, Ng et al., 2003Ng H.H. Robert F. Young R.A. Struhl K. Targeted recruitment of Set1 histone methylase by elongating Pol II provides a localized mark and memory of recent transcriptional activity.Mol. Cell. 2003; 11: 709-719Abstract Full Text Full Text PDF PubMed Scopus (804) Google Scholar, Schneider et al., 2004Schneider R. Bannister A.J. Myers F.A. Thorne A.W. Crane-Robinson C. Kouzarides T. Histone H3 lysine 4 methylation patterns in higher eukaryotic genes.Nat. Cell Biol. 2004; 6: 73-77Crossref PubMed Scopus (562) Google Scholar, Schubeler et al., 2004Schubeler D. MacAlpine D.M. Scalzo D. Wirbelauer C. Kooperberg C. van Leeuwen F. Gottschling D.E. O'Neill L.P. Turner B.M. Delrow J. et al.The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote.Genes Dev. 2004; 18: 1263-1271Crossref PubMed Scopus (600) Google Scholar, Bernstein et al., 2005Bernstein B.E. Kamal M. Lindblad-Toh K. Bekiranov S. Bailey D.K. Huebert D.J. McMahon S. Karlsson E.K. Kulbokas 3rd, E.J. Gingeras T.R. et al.Genomic maps and comparative analysis of histone modifications in human and mouse.Cell. 2005; 120: 169-181Abstract Full Text Full Text PDF PubMed Scopus (1084) Google Scholar, Pokholok et al., 2005Pokholok D.K. Harbison C.T. Levine S. Cole M. Hannett N.M. Lee T.I. Bell G.W. Walker K. Rolfe P.A. Herbolsheimer E. et al.Genome-wide map of nucleosome acetylation and methylation in yeast.Cell. 2005; 122: 517-527Abstract Full Text Full Text PDF PubMed Scopus (1010) Google Scholar). The emerging consensus is that high levels of H3K4 trimethylation are associated with the 5′ regions of virtually all active genes and that there is a strong positive correlation between this modification, transcription rates, active polymerase II occupancy, and histone acetylation (Santos-Rosa et al., 2002Santos-Rosa H. Schneider R. Bannister A.J. Sherriff J. Bernstein B.E. Emre N.C. Schreiber S.L. Mellor J. Kouzarides T. Active genes are tri-methylated at K4 of histone H3.Nature. 2002; 419: 407-411Crossref PubMed Scopus (1431) Google Scholar, Ng et al., 2003Ng H.H. Robert F. Young R.A. Struhl K. Targeted recruitment of Set1 histone methylase by elongating Pol II provides a localized mark and memory of recent transcriptional activity.Mol. Cell. 2003; 11: 709-719Abstract Full Text Full Text PDF PubMed Scopus (804) Google Scholar, Schneider et al., 2004Schneider R. Bannister A.J. Myers F.A. Thorne A.W. Crane-Robinson C. Kouzarides T. Histone H3 lysine 4 methylation patterns in higher eukaryotic genes.Nat. Cell Biol. 2004; 6: 73-77Crossref PubMed Scopus (562) Google Scholar, Schubeler et al., 2004Schubeler D. MacAlpine D.M. Scalzo D. Wirbelauer C. Kooperberg C. van Leeuwen F. Gottschling D.E. O'Neill L.P. Turner B.M. Delrow J. et al.The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote.Genes Dev. 2004; 18: 1263-1271Crossref PubMed Scopus (600) Google Scholar, Bernstein et al., 2005Bernstein B.E. Kamal M. Lindblad-Toh K. Bekiranov S. Bailey D.K. Huebert D.J. McMahon S. Karlsson E.K. Kulbokas 3rd, E.J. Gingeras T.R. et al.Genomic maps and comparative analysis of histone modifications in human and mouse.Cell. 2005; 120: 169-181Abstract Full Text Full Text PDF PubMed Scopus (1084) Google Scholar, Pokholok et al., 2005Pokholok D.K. Harbison C.T. Levine S. Cole M. Hannett N.M. Lee T.I. Bell G.W. Walker K. Rolfe P.A. Herbolsheimer E. et al.Genome-wide map of nucleosome acetylation and methylation in yeast.Cell. 2005; 122: 517-527Abstract Full Text Full Text PDF PubMed Scopus (1010) Google Scholar). In contrast, patterns of dimethyl H3K4 differ significantly between yeast and vertebrate chromatin: in S. cerevisiae, dimethylated H3K4 appears to spread throughout genes, peaking toward the middle of the coding region, and is associated with a transcriptionally “poised” as well as active state, with monomethylation most abundant at 3′ ends of genes (Santos-Rosa et al., 2002Santos-Rosa H. Schneider R. Bannister A.J. Sherriff J. Bernstein B.E. Emre N.C. Schreiber S.L. Mellor J. Kouzarides T. Active genes are tri-methylated at K4 of histone H3.Nature. 2002; 419: 407-411Crossref PubMed Scopus (1431) Google Scholar, Ng et al., 2003Ng H.H. Robert F. Young R.A. Struhl K. Targeted recruitment of Set1 histone methylase by elongating Pol II provides a localized mark and memory of recent transcriptional activity.Mol. Cell. 2003; 11: 709-719Abstract Full Text Full Text PDF PubMed Scopus (804) Google Scholar, Pokholok et al., 2005Pokholok D.K. Harbison C.T. Levine S. Cole M. Hannett N.M. Lee T.I. Bell G.W. Walker K. Rolfe P.A. Herbolsheimer E. et al.Genome-wide map of nucleosome acetylation and methylation in yeast.Cell. 2005; 122: 517-527Abstract Full Text Full Text PDF PubMed Scopus (1010) Google Scholar). Whereas in vertebrates, the majority of H3K4 dimethylation colocalizes with H3K4 trimethylation in discrete zones about 5–20 nucleosomes in length proximate to highly transcribed genes (Schneider et al., 2004Schneider R. Bannister A.J. Myers F.A. Thorne A.W. Crane-Robinson C. Kouzarides T. Histone H3 lysine 4 methylation patterns in higher eukaryotic genes.Nat. Cell Biol. 2004; 6: 73-77Crossref PubMed Scopus (562) Google Scholar, Bernstein et al., 2005Bernstein B.E. Kamal M. Lindblad-Toh K. Bekiranov S. Bailey D.K. Huebert D.J. McMahon S. Karlsson E.K. Kulbokas 3rd, E.J. Gingeras T.R. et al.Genomic maps and comparative analysis of histone modifications in human and mouse.Cell. 2005; 120: 169-181Abstract Full Text Full Text PDF PubMed Scopus (1084) Google Scholar). Interestingly, a subset of dimethylated sites is devoid of trimethylation (Bernstein et al., 2005Bernstein B.E. Kamal M. Lindblad-Toh K. Bekiranov S. Bailey D.K. Huebert D.J. McMahon S. Karlsson E.K. Kulbokas 3rd, E.J. Gingeras T.R. et al.Genomic maps and comparative analysis of histone modifications in human and mouse.Cell. 2005; 120: 169-181Abstract Full Text Full Text PDF PubMed Scopus (1084) Google Scholar). These isolated H3K4 dimethylated regions do not correlate with transcription start sites, and their presence is highly dependent on the cell type tested, suggesting that they may have a role in determining lineage-specific chromatin states over genomic regulatory elements (Bernstein et al., 2005Bernstein B.E. Kamal M. Lindblad-Toh K. Bekiranov S. Bailey D.K. Huebert D.J. McMahon S. Karlsson E.K. Kulbokas 3rd, E.J. Gingeras T.R. et al.Genomic maps and comparative analysis of histone modifications in human and mouse.Cell. 2005; 120: 169-181Abstract Full Text Full Text PDF PubMed Scopus (1084) Google Scholar). Although H3K4 methylation of mammalian genomes is generally localized to punctate sites, a unique pattern of H3K4 methylation was observed in Hox gene clusters, where large regions of continuous H3K4 methylation spanning multiple genes and intergenic regions are observed (Guenther et al., 2005Guenther M.G. Jenner R.G. Chevalier B. Nakamura T. Croce C.M. Canaani E. Young R.A. Global and Hox-specific roles for the MLL1 methyltransferase.Proc. Natl. Acad. Sci. USA. 2005; 102: 8603-8608Crossref PubMed Scopus (254) Google Scholar, Bernstein et al., 2005Bernstein B.E. Kamal M. Lindblad-Toh K. Bekiranov S. Bailey D.K. Huebert D.J. McMahon S. Karlsson E.K. Kulbokas 3rd, E.J. Gingeras T.R. et al.Genomic maps and comparative analysis of histone modifications in human and mouse.Cell. 2005; 120: 169-181Abstract Full Text Full Text PDF PubMed Scopus (1084) Google Scholar). These extended methylation regions depended on the cell lineage tested and correlate with the activation status of the underlying Hox gene. One possibility is that extended H3K4 methylation domains may simply reflect transcriptional activity, including transcription through the intergenic regions (Bae et al., 2002Bae E. Calhoun V.C. Levine M. Lewis E.B. Drewell R.A. Characterization of the intergenic RNA profile at abdominal-A and Abdominal-B in the Drosophila bithorax complex.Proc. Natl. Acad. Sci. USA. 2002; 99: 16847-16852Crossref PubMed Scopus (111) Google Scholar, Rank et al., 2002Rank G. Prestel M. Paro R. Transcription through intergenic chromosomal memory elements of the Drosophila bithorax complex correlates with an epigenetic switch.Mol. Cell. Biol. 2002; 22: 8026-8034Crossref PubMed Scopus (124) Google Scholar, Bernstein et al., 2005Bernstein B.E. Kamal M. Lindblad-Toh K. Bekiranov S. Bailey D.K. Huebert D.J. McMahon S. Karlsson E.K. Kulbokas 3rd, E.J. Gingeras T.R. et al.Genomic maps and comparative analysis of histone modifications in human and mouse.Cell. 2005; 120: 169-181Abstract Full Text Full Text PDF PubMed Scopus (1084) Google Scholar). However, other evidence suggests that H3K4 methylation may in fact precede transcription of late Hox genes during embryonic stem cell differentiation (Chambeyron and Bickmore, 2004Chambeyron S. Bickmore W.A. Chromatin decondensation and nuclear reorganization of the HoxB locus upon induction of transcription.Genes Dev. 2004; 18: 1119-1130Crossref PubMed Scopus (486) Google Scholar). Furthermore, a recent study in Drosophila suggests a complex role for the H3K4 methyltransferase Trithorax (Trx) in balancing both positive and negative regulation of Hox gene expression, involving promoting transcription of the noncoding RNAs at the Hox loci (Petruk et al., 2006Petruk S. Sedkov Y. Riley K.M. Hodgson J. Schweisguth F. Hirose S. Jaynes J.B. Brock H.W. Mazo A. Transcription of bxd noncoding RNAs promoted by Trithorax represses Ubx in cis by transcriptional interference.Cell. 2006; 127: 1209-1220Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar). Curiously, loss of proteins that control global levels of K4 methylation in higher organisms results in relatively specific developmental phenotypes, in particular, defects in control of Hox gene expression (Byrd and Shearn, 2003Byrd K.N. Shearn A. ASH1, a Drosophila trithorax group protein, is required for methylation of lysine 4 residues on histone H3.Proc. Natl. Acad. Sci. USA. 2003; 100: 11535-11540Crossref PubMed Scopus (106) Google Scholar, Wysocka et al., 2005Wysocka J. Swigut T. Milne T.A. Dou Y. Zhang X. Burlingame A.L. Roeder R.G. Brivanlou A.H. Allis C.D. WDR5 associates with histone H3 methylated at K4 and is essential for H3 K4 methylation and vertebrate development.Cell. 2005; 121: 859-872Abstract Full Text Full Text PDF PubMed Scopus (585) Google Scholar). Although H3K4 methylation-independent roles for these proteins cannot be excluded, we hypothesize that these defects result from an enhanced effect of H3K4 methylation on gene expression patterns within developmental gene clusters, consonant with the unique methylation patterns within these domains. Whether H3K4 methylation within developmental gene clusters contributes to the maintenance of the higher-order chromatin structure, e.g., by counteracting the silencing effects of the Polycomb group proteins (Klymenko and Muller, 2004Klymenko T. Muller J. The histone methyltransferases Trithorax and Ash1 prevent transcriptional silencing by Polycomb group proteins.EMBO Rep. 2004; 5: 373-377Crossref PubMed Scopus (184) Google Scholar), remains an interesting area for future investigations. The majority of histone lysine methyltransferases contain a SET domain, which catalyzes the addition of methyl groups to the specific lysine residues (for reviews, see Dillon et al., 2005Dillon S.C. Zhang X. Trievel R.C. Cheng X. The SET-domain protein superfamily: protein lysine methyltransferases.Genome Biol. 2005; 6: 227Crossref PubMed Scopus (461) Google Scholar and Martin and Zhang, 2005Martin C. Zhang Y. The diverse functions of histone lysine methylation.Nat. Rev. Mol. Cell Biol. 2005; 6: 838-849Crossref PubMed Scopus (1419) Google Scholar). The first H3K4 methyltransferase to be identified was S. cerevisiae Set1, the sole enzyme responsible for H3K4 methylation in yeast (Briggs et al., 2001Briggs S.D. Bryk M. Strahl B.D. Cheung W.L. Davie J.K. Dent S.Y. Winston F. Allis C.D. Histone H3 lysine 4 methylation is mediated by Set1 and required for cell growth and rDNA silencing in Saccharomyces cerevisiae.Genes Dev. 2001; 15: 3286-3295Crossref PubMed Scopus (446) Google Scholar, Roguev et al., 2001Roguev A. Schaft D. Shevchenko A. Pijnappel W.W. Wilm M. Aasland R. Stewart A.F. The Saccharomyces cerevisiae Set1 complex includes an Ash2 homologue and methylates histone 3 lysine 4.EMBO J. 2001; 20: 7137-7148Crossref PubMed Scopus (415) Google Scholar). In mammals, the complexity of methyl writers is greater, in that at least ten known or predicted H3K4 methyltransferases exist (see Figure 1A). The catalytic SET domains of these proteins are either related to the yeast Set1 and Drosophila Trx (as in the case of six MLL-family members discussed later) or unrelated, as in the case of ASH1 (Beisel et al., 2002Beisel C. Imhof A. Greene J. Kremmer E. Sauer F. Histone methylation by the Drosophila epigenetic transcriptional regulator Ash1.Nature. 2002; 419: 857-862Crossref PubMed Scopus (234) Google Scholar), SET7/9 (Wang et al., 2001Wang H. Cao R. Xia L. Erdjument-Bromage H. Borchers C. Tempst P. Zhang Y. Purification and functional characterization of a histone H3-lysine 4-specific methyltransferase.Mol. Cell. 2001; 8: 1207-1217Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar, Nishioka et al., 2002Nishioka K. Rice J.C. Sarma K. Erdjument-Bromage H. Werner J. Wang Y. Chuikov S. Valenzuela P. Tempst P. Steward R. et al.PR-Set7 is a nucleosome-specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin.Mol. Cell. 2002; 9: 1201-1213Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar), SMYD3 (Hamamoto et al., 2004Hamamoto R. Furukawa Y. Morita M. Iimura Y. Silva F.P. Li M. Yagyu R. Nakamura Y. SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells.Nat. Cell Biol. 2004; 6: 731-740Crossref PubMed Scopus (549) Google Scholar), and Meisetz (Hayashi et al., 2005Hayashi K. Yoshida K. Matsui Y. A histone H3 methyltransferase controls epigenetic events required for meiotic prophase.Nature. 2005; 438: 374-378Crossref PubMed Scopus (334) Google Scholar). The structural and mechanistic aspects of the catalytic methyltransferase domains have been extensively reviewed (Marmorstein, 2003Marmorstein R. Structure of SET domain proteins: a new twist on histone methylation.Trends Biochem. Sci. 2003; 28: 59-62Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, Cheng et al., 2005Cheng X. Collins R.E. Zhang X. Structural and sequence motifs of protein (histone) methylation enzymes.Annu. Rev. Biophys. Biomol. Struct. 2005; 34: 267-294Crossref PubMed Scopus (246) Google Scholar, Xiao et al., 2005Xiao B. Jing C. Kelly G. Walker P.A. Muskett F.W. Frenkiel T.A. Martin S.R. Sarma K. Reinberg D. Gamblin S.J. Wilson J.R. Specificity and mechanism of the histone methyltransferase Pr-Set7.Genes Dev. 2005; 19: 1444-1454Crossref PubMed Scopus (140) Google Scholar) and will not be discussed further. Bioinformatic analysis of human SET domain-containing proteins reveals the existence of multiple SET domain homology clusters; the cluster of S. cerevisiae Set1 and Drosophila Trx-related SET domains contains Mixed Lineage Leukemia 1 (MLL1) and five other proteins, MLL2, MLL3, MLL4, SET1A, and SET1B (Glaser et al., 2006Glaser S. Schaft J. Lubitz S. Vintersten K. van der Hoeven F. Tufteland K.R. Aasland R. Anastassiadis K. Ang S.L. Stewart A.F. Multiple epigenetic maintenance factors implicated by the loss of Mll2 in mouse development.Development. 2006; 133: 1423-1432Crossref PubMed Scopus (201) Google Scholar; T. Swigut and J.W., unpublished data), which we will collectively refer to as the MLL family (Figure 1A). Five of the six MLL-family proteins, MLL1–MLL4 and SET1A, have already been shown to display H3K4 methyltransferase activity (Milne et al., 2002Milne T.A. Briggs S.D. Brock H.W. Martin M.E. Gibbs D. Allis C.D. Hess J.L. MLL targets SET domain methyltransferase activity to Hox gene promoters.Mol. Cell. 2002; 10: 1107-1117Abstract Full Text Full Text PDF PubMed Scopus (781) Google Scholar, Wysocka et al., 2003Wysocka J. Myers M.P. Laherty C.D. Eisenman R.N. Herr W. Human Sin3 deacetylase and trithorax-related Set1/Ash2 histone H3-K4 methyltransferase are tethered together selectively by the cell-proliferation factor HCF-1.Genes Dev. 2003; 17: 896-911Crossref PubMed Scopus (295) Google Scholar, Goo et al., 2003Goo Y.-H. Sohn Y.C. Kim D.-H. Kim S.-W. Kang M.-J. Jung D.-J. Kwak E. Barlev N.A. Berger S.L. Chow V.T. et al.Activating signal cointegrator 2 belongs to a novel steady-state complex that contains a subset of trithorax group proteins.Mol. Cell. Biol. 2003; 23: 140-149Crossref PubMed Scopus (169) Google Scholar, Hughes et al., 2004Hughes C.M. Rozenblatt-Rosen O. Milne T.A. Copeland T.D. Levine S.S. Lee J.C. Hayes D.N. Shanmugam K.S. Bhattacharjee A. Biondi C.A. et al.Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus.Mol. Cell. 2004; 13: 587-597Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar, Yokoyama et al., 2004Yokoyama A. Wang Z. Wysocka J. Sanyal M. Aufiero D.J. Kitabayashi I. Herr W. Cleary M.L. Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression.Mol. Cell. Biol. 2004; 24: 5639-5649Crossref PubMed Scopus (482) Google Scholar), raising the intriguing question of why yeast can accomplish this task with only one enzyme while humans require multiple enzymatic isoforms. The multiplicity of Trx-related methyltransferases in vertebrate genomes likely results from their functional specialization either through differential expression patterns, recruitment to different gene targets, as a consequence of their SET domain-independent functions, or methylation of distinct nonhistone substrates. The distinguishable phenotypes of deletions or truncations in Mll1, Mll2, and Mll3 genes in mice suggests that MLL proteins are not redundant in their function but instead are specialized to deal with the regulatory complexity of vertebrate development (Yu et al., 1995Yu B.D. Hess J.L. Horning S.E. Brown G.A. Korsmeyer S.J. Altered Hox expression and segmental identity in Mll-mutant mice.Nature. 1995; 378: 505-508Crossref PubMed Scopus (680) Google Scholar, Glaser et al., 2006Glaser S. Schaft J. Lubitz S. Vintersten K. van der Hoeven F. Tufteland K.R. Aasland R. Anastassiadis K. Ang S.L. Stewart A.F. Multiple epigenetic maintenance factors implicated by the loss of Mll2 in mouse development.Development. 2006; 133: 1423-1432Crossref PubMed Scopus (201) Google Scholar, Lee et al., 2006Lee S. Lee D.-K. Dou Y. Lee J. Lee B. Kwak E. Kong Y.-Y. Lee S.-K. Roeder R.G. Lee J.W. Coactivator as a target gene specificity determinant for histone H3 lysine 4 methyltransferases.Proc. Natl. Acad. Sci. USA. 2006; 103: 15392-15397Crossref PubMed Scopus (113) Google Scholar). Like Drosophila Trx, mammalian MLL1 and MLL2 have a role in long-term maintenance of Hox gene expression patterns during development (Yu et al., 1995Yu B.D. Hess J.L. Horning S.E. Brown G.A. Korsmeyer S.J. Altered Hox expression and segmental identity in Mll-mutant mice.Nature. 1995; 378: 505-508Crossref PubMed Scopus (680) Google Scholar, Glaser et al., 2006Glaser S. Schaft J. Lubitz S. Vintersten K. van der Hoeven F. Tufteland K.R. Aasland R. Anastassiadis K. Ang S.L. Stewart A.F. Multiple epigenetic maintenance factors implicated by the loss of Mll2 in mouse development.Development. 2006; 133: 1423-1432Crossref PubMed Scopus (201) Google Scholar). A recent genetic study in mice demonstrated that deletion of the MLL1 SET domain results in a homeotic phenotype, strongly suggesting a role for H3K4 methylation in the regulation of epigenetic memory in mammals (Terranova et al., 2006Terranova R. Agherbi H. Boned A. Meresse S. Djabali M. Histone and DNA methylation defects at Hox genes in mice expressing a SET domain-truncated form of Mll.Proc. Natl. Acad. Sci. USA. 2006; 103: 6629-6634Crossref PubMed Scopus (141) Google Scholar). Importantly, rearrangements of the MLL1 gene in humans are associated with a variety of aggressive human leukemias in both children and adults, and the disregulation of Hox genes caused by MLL1 fusion proteins appears to play a central role in this transformation (for review, see Hess, 2004Hess J.L. Mechanisms of transformation by MLL.Crit. Rev. Eukaryot. Gene Expr. 2004; 14: 235-254Crossref PubMed Scopus (70) Google Scholar). Like most histone-modifying enzymes, the MLL-family methyltransferases exist in multiprotein complexes. MLL-family complexes share, but are not limited to, three common subunits: WDR5, RbPB5, and ASH2 (Milne et al., 2002Milne T.A. Briggs S.D. Brock H.W. Martin M.E. Gibbs D. Allis C.D. Hess J.L. MLL targets SET domain methyltransferase activity to Hox gene promoters.Mol. Cell. 2002; 10: 1107-1117Abstract Full Text Full Text PDF PubMed Scopus (781) Google Scholar, Wysocka et al., 2003Wysocka J. Myers M.P. Laherty C.D. Eisenman R.N. Herr W. Human Sin3 deacetylase and trithorax-related Set1/Ash2 histone H3-K4 methyltransferase are tethered together selectively by the cell-proliferation factor HCF-1.Genes Dev. 2003; 17: 896-911Crossref PubMed Scopus (295) Google Scholar, Hughes et al., 2004Hughes C.M. Rozenblatt-Rosen O. Milne T.A. Copeland T.D. Levine S.S. Lee J.C. Hayes D.N. Shanmugam K.S. Bhattacharjee A. Biondi C.A. et al.Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus.Mol. Cell. 2004; 13: 587-597Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar, Yokoyama et al., 2004Yokoyama A. Wang Z. Wysocka J. Sanyal M. Aufiero D.J. Kitabayashi I. Herr W. Cleary M.L. Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression.Mol. Cell. Biol. 2004; 24: 5639-5649Crossref PubMed Scopus (482) Google Scholar, Lee and Skalnik, 2005Lee J.H. Skalnik D.G. CpG-binding protein (CXXC finger protein 1) is a component of the mammalian Set1 histone H3-Lys4 methyltransferase complex, the analogue of the yeast Set1/COMPASS complex.J. Biol. Chem. 2005; 280: 41725-41731Crossref PubMed Scopus (219) Google Scholar). Recent biochemical reconstitution of the four-component MLL1 core complex revealed that recombinant WDR5, RbBP5, ASH2, and a portion of MLL1 are sufficient for recapitulating H3K4 methyltransferase activity comparable to that of the MLL1 holocomplex purified from human cells (Dou et al., 2006Dou Y. Milne T.A. Ruthenburg A.J. Lee S. Lee J.W. Verdine G.L. Allis C.D. Roeder R.G. Regulation of MLL1 H3K4 methyltransferase activity by its core components.Nat. Struct. Mol. Biol. 2006; 13: 713-719Crossref PubMed Scopus (481) Google Scholar). Importantly, the WDR5/RbBP5/ASH2 subcomplex associates with the MLL1 SET domain but can exist independently of the catalytic subunit, providing a structural platform that can associate with the SET domains of different MLL-family members (Dou et al., 2006Dou Y. Milne T.A. Ruthenburg A.J. Lee S. Lee J.W. Verdine G.L. Allis C.D. Roeder R.G. Regulation of MLL1 H3K4 methyltransferase activity by its core components.Nat. Struct. Mol. Biol. 2006; 13: 713-719Crossref PubMed Scopus (481) Google Scholar; see Figure 1B). All three subcomplex components are required for H3K4 methylation by MLL1 in vitro and in vivo (Dou et al., 2006Dou Y. Milne T.A. Ruthenburg A.J. Lee S. Lee J.W. Verdine G.L. Allis C.D. Roeder R.G. Regulation of MLL1 H3K4 methyltransferase activity by its core components.Nat. Struct. Mol. 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Biol. 2006; 13: 852-854Crossref PubMed Scopus (232) Google Scholar). Whereas the four-component minimal complex provides a catalytic engine for H3K4 methylation, several biochemically purified MLL-family complexes also contain other subunits, including cell proliferation regulator HCF-1 and tumor suppressor menin (Wysocka et al., 2003Wysocka J. Myers M.P. Laherty C.D. Eisenman R.N. Herr W. Human Sin3 deacetylase and trithorax-related Set1/Ash2 histone H3-K4 methyltransferase are tethered together selectively by the cell-proliferation factor HCF-1.Genes Dev. 2003; 17: 896-911Crossref" @default.
• W2024584416 created "2016-06-24" @default.
• W2024584416 creator A5052967210 @default.
• W2024584416 creator A5067756497 @default.
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• W2024584416 date "2007-01-01" @default.
• W2024584416 modified "2023-10-16" @default.
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