Structural Basis for the Requirement of Additional Factors for MLL1 SET Domain Activity and Recognition of Epigenetic Marks

Southall, Stacey M.; Wong, P.S.; Odho, Z.; Roe, S. Mark; Wilson, J.

doi:10.1016/j.molcel.2008.12.029

Cited by 207 publications

(281 citation statements)

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“…In mammals, a "phospho/methyl switch," where phosphorylation of a histone residue may affect the readout of a stable methylation mark in a neighboring residue, has been proposed to operate at the H3T3/K4 site (13,14,37,38). However, H3K4 methylation by the mixed-lineage leukemia 1 protein in vitro is strongly reduced by H3T3ph (39). Conversely, the activity of Haspin and AtHaspin is inhibited by H3K4me3 (40,41).…”

Section: Discussionmentioning

confidence: 99%

Osmotic stress induces phosphorylation of histone H3 at threonine 3 in pericentromeric regions of Arabidopsis thaliana

Wang

Casas-Mollano

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

132

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Histone phosphorylation plays key roles in stress-induced transcriptional reprogramming in metazoans but its function(s) in land plants has remained relatively unexplored. Here we report that an Arabidopsis mutant defective in At3g03940 and At5g18190, encoding closely related Ser/Thr protein kinases, shows pleiotropic phenotypes including dwarfism and hypersensitivity to osmotic/salt stress. The double mutant has reduced global levels of phosphorylated histone H3 threonine 3 (H3T3ph), which are not enhanced, unlike the response in the wild type, by drought-like treatments. Genome-wide analyses revealed increased H3T3ph, slight enhancement in trimethylated histone H3 lysine 4 (H3K4me3), and a modest decrease in histone H3 occupancy in pericentromeric/knob regions of wild-type plants under osmotic stress. However, despite these changes in heterochromatin, transposons and repeats remained transcriptionally repressed. In contrast, this reorganization of heterochromatin was mostly absent in the double mutant, which exhibited lower H3T3ph levels in pericentromeric regions even under normal environmental conditions. Interestingly, within actively transcribed protein-coding genes, H3T3ph density was minimal in 5′ genic regions, coincidental with a peak of H3K4me3 accumulation. This pattern was not affected in the double mutant, implying the existence of additional H3T3 protein kinases in Arabidopsis. Our results suggest that At3g03940 and At5g18190 are involved in the phosphorylation of H3T3 in pericentromeric/knob regions and that this repressive epigenetic mark may be important for maintaining proper heterochromatic organization and, possibly, chromosome function(s).epigenetics | heterochromatin | histone phosphorylation | abiotic stress | protein kinase

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Section: Discussionmentioning

confidence: 99%

Osmotic stress induces phosphorylation of histone H3 at threonine 3 in pericentromeric regions of Arabidopsis thaliana

Wang

Casas-Mollano

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

132

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“…Phosphorylation of RbBP5 on S350 potentiates WRAD assembly MLL1 is tightly regulated by various mechanisms, including allosteric regulation by the WRAD complex (Dou et al 2006), deposition of other post-translational modifications on histone proteins (Southall et al 2009), and phosphorylation of MLL1 by ATR . In the RbBP5 D/E box (Supplemental Fig.…”

Section: Disruption Of Ash2l/rbbp5 Interaction Impairs Mll1 Enzymaticmentioning

confidence: 99%

A phosphorylation switch on RbBP5 regulates histone H3 Lys4 methylation

et al. 2015

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The methyltransferase activity of the trithorax group (TrxG) protein MLL1 found within its COMPASS (complex associated with SET1)-like complex is allosterically regulated by a four-subunit complex composed of WDR5, RbBP5, Ash2L, and DPY30 (also referred to as WRAD). We report structural evidence showing that in WRAD, a concave surface of the Ash2L SPIa and ryanodine receptor (SPRY) domain binds to a cluster of acidic residues, referred to as the D/E box, in RbBP5. Mutational analysis shows that residues forming the Ash2L/RbBP5 interface are important for heterodimer formation, stimulation of MLL1 catalytic activity, and erythroid cell terminal differentiation. We also demonstrate that a phosphorylation switch on RbBP5 stimulates WRAD complex formation and significantly increases KMT2 (lysine [K] methyltransferase 2) enzyme methylation rates. Overall, our findings provide structural insights into the assembly of the WRAD complex and point to a novel regulatory mechanism controlling the activity of the KMT2/COMPASS family of lysine methyltransferases.Supplemental material is available for this article.Received October 27, 2014; revised version accepted December 15, 2014. The methyltransferase activity of the trithorax group (TrxG) protein MLL1 as well as the other members of the KMT2 (lysine [K] methyltransferase 2) family found within COMPASS (complex associated with SET1) catalyzes the site-specific methylation of the e-amine of Lys4 (K4) of histone H3 (Shilatifard 2012). While these enzymes share the ability to methylate the same residue on histone H3, the catalytic activity of these enzymes is linked to different biological processes. MLL1/MLL2 di/trimethylate H3K4 (H3K4me2/3) and regulate Hox gene expression during embryonic development (Yu et al. 1995;Dou et al. 2006). MLL3/MLL4 regulate adipogenesis ) and primarily monomethylate H3K4 (H3K4me1) at both enhancer (Herz et al. 2012;Hu et al. 2013) and promoter (Cheng et al. 2014) regions, while SET1A/B are the primary H3K4 trimethyltransferases (Wu et al. 2008). However, despite divergence in catalytic activity and functional roles, enzymes of the KMT2/COMPASS family must assemble into multisubunit complexes to carry out their biological functions.Our molecular understanding of the protein complexes involved in H3K4 methylation stems from the isolation of COMPASS from Saccharomyces cerevisiae (Miller et al. 2001;Roguev et al. 2001;Krogan et al. 2002;Dehe et al. 2006). These studies demonstrated that regulatory subunits found within COMPASS and mammalian COMPASS-like complexes play key roles in stabilizing the enzyme and stimulating its methyltransferase activity as well as targeting the protein complex to specific genomic loci (Couture and Skiniotis 2013). While each of these multisubunit protein complexes contains unique subunits, each member of the KMT2 family associates with a common set of four evolutionarily conserved regulatory proteins; namely, WDR5, RbBP5, Ash2L, and DPY30 (WRAD) (Couture and Skiniotis 2013). The foursubunit complex directly binds ...

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“…25 MLL C then associates with at least four proteins, that is, the histone acetyltransferase MYST1(MOF), 26 and WDR5, RBBP5 and ASH2L, to ensure histone modification and methyltransferase activity. 27 The MLL N fragment has a binding site for MEN1 at the N-terminal end and both recruit PSIP1(LEDGF). 28 PSIP1 then contacts the chromatin by a PWWP domain.…”

Section: Etiology Of Mll Rearrangementsmentioning

confidence: 99%

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

et al. 2011

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Translocations involving the mixed-lineage leukemia (MLL) gene, localized at 11q23, comprise 15 to 20% of all pediatric acute myeloid leukemia (AML) cases. This review summarizes current knowledge about the etiology, biology, clinical characteristics and differences in outcome in MLL-rearranged pediatric AML. Furthermore, we discuss the role of cooperating events in MLL-rearranged pediatric AML, and future therapeutic strategies to improve outcome. We conclude that MLL-rearranged pediatric AML is a heterogeneous disease, and prognosis depends on various factors, for example, translocation partner, age, WBC and additional cytogenetic aberrations. The relationship of outcome with specific translocation partners requires that they be searched for in the diagnostic work-up of AML. To achieve further improvements in outcome, unraveling the biology of MLL-rearranged pediatric AML is warranted.

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Structural Basis for the Requirement of Additional Factors for MLL1 SET Domain Activity and Recognition of Epigenetic Marks

Cited by 207 publications

References 54 publications

Osmotic stress induces phosphorylation of histone H3 at threonine 3 in pericentromeric regions of Arabidopsis thaliana

Osmotic stress induces phosphorylation of histone H3 at threonine 3 in pericentromeric regions of Arabidopsis thaliana

A phosphorylation switch on RbBP5 regulates histone H3 Lys4 methylation

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

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