An H3K9/S10 methyl-phospho switch modulates Polycomb and Pol II binding at repressed genes during differentiation

Sabbattini, Pierangela; Sjöberg, Marcela; Nikic, Svetlana; Frangini, Alberto; Holmqvist, Per-Henrik; Kunowska, Natalia; Carroll, Tom; Brookes, Emily; Arthur, J. Simon C.; Pombo, Ana; Dillon, Niall

doi:10.1091/mbc.e13-10-0628

Cited by 35 publications

(38 citation statements)

References 34 publications

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“…All of these substrates can, potentially, alter gene expression. The choice of which substrate, or even which lysine, to phosphorylate is likely to be context dependent [45, 46]. The catalytic properties of Msk1, previous data and the present results suggest that the enzyme regulates the KMT2A/MLL1 complex in one or both of two general ways, namely by enhancing SET domain-catalysed H3K4 methylation and/or by allowing the complex to access condensed chromatin.…”

Section: Discussionmentioning

confidence: 73%

“…Genes can be protected against PRC2-mediated silencing by H3K27 acetylation [56], and by modification of other H3 lysines [46, 57–59], but phosphorylation of H3 at serine 28, catalysed by MSK1/2, is known to displace PRC2, presumably by disrupting binding to the adjacent, methylated residue [60, 61]. This is consistent with the increase in H3K28ph abundance observed at the promoter regions of genes that are transcriptionally activated when quiescent 3T3 cells are stimulated back into growth [62].…”

Section: Discussionmentioning

confidence: 99%

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Protein kinase Msk1 physically and functionally interacts with the KMT2A/MLL1 methyltransferase complex and contributes to the regulation of multiple target genes

Wiersma

Bussière

Halsall

et al. 2016

Epigenetics & Chromatin

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BackgroundThe KMT2A/MLL1 lysine methyltransferase complex is an epigenetic regulator of selected developmental genes, in part through the SET domain-catalysed methylation of H3K4. It is essential for normal embryonic development and haematopoiesis and frequently mutated in cancer. The catalytic properties and targeting of KMT2A/MLL1 depend on the proteins with which it complexes and the post-translational protein modifications which some of these proteins put in place, though detailed mechanisms remain unclear.ResultsKMT2A/MLL1 (both native and FLAG-tagged) and Msk1 (RPS6KA5) co-immunoprecipitated in various cell types. KMT2A/MLL1 and Msk1 knockdown demonstrated that the great majority of genes whose activity changed on KTM2A/MLL1 knockdown, responded comparably to Msk1 knockdown, as did levels of H3K4 methylation and H3S10 phosphorylation at KTM2A target genes HoxA4, HoxA5. Knockdown experiments also showed that KMT2A/MLL1 is required for the genomic targeting of Msk1, but not vice versa.ConclusionThe KMT2A/MLL1 complex is associated with, and functionally dependent upon, the kinase Msk1, part of the MAP kinase signalling pathway. We propose that Msk1-catalysed phosphorylation at H3 serines 10 and 28, supports H3K4 methylation by the KMT2A/MLL1 complex both by making H3 a more attractive substrate for its SET domain, and improving target gene accessibility by prevention of HP1- and Polycomb-mediated chromatin condensation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-016-0103-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Protein kinase Msk1 physically and functionally interacts with the KMT2A/MLL1 methyltransferase complex and contributes to the regulation of multiple target genes

Wiersma

Bussière

Halsall

et al. 2016

Epigenetics & Chromatin

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“…Chromatin condensation in naive, quiescent T cells is mediated, at least in part, by the activity of condensi n 2, which is also involved in condensing mitotic chromo somes 85 double H3K9me3-H3S10ph (H3S10 phosphorylation) and H3K27me3-H3S28ph modifications, which are not present in activated or terminally differentiated B cells, and are instead reminiscent of the epigenetic profile of metaphase chromosomes 86 . Quiescent resting lymphocytes have greatly reduced levels of transcription compared with activated lymphocytes 87 , and it is tempting to link this feature with the increase in chromatin condensation found in the resting cells.…”

Section: Nuclear Organization and Cell Functionmentioning

confidence: 99%

Three-dimensional genome architecture: players and mechanisms

Pombo

Dillon

2015

Nat Rev Mol Cell Biol

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397

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The different cell types of an organism share the same DNA, but during cell differentiation their genomes undergo diverse structural and organizational changes that affect gene expression and other cellular functions. These can range from large-scale folding of whole chromosomes or of smaller genomic regions, to the re-organization of local interactions between enhancers and promoters, mediated by the binding of transcription factors and chromatin looping. The higher-order organization of chromatin is also influenced by the specificity of the contacts that it makes with nuclear structures such as the lamina. Sophisticated methods for mapping chromatin contacts are generating genome-wide data that provide deep insights into the formation of chromatin interactions, and into their roles in the organization and function of the eukaryotic cell nucleus.

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“…The condensed chromatin is characterized by a mitosis-typical co-localization of phosphorylated serine 10 and trimethylated lysine 9 on histone 3 (H3S10p and H3K9me3). This modification may be involved in developmentally regulated gene regulation (28) but the primary biological function of MLCC in cancer cells has remained unclear. Furthermore, the data suggest that MLCC physically protects genomic DNA against the induction of lethal DNA double-strand breaks (DSB) by IR (27).…”

Section: Introductionmentioning

confidence: 99%

Radiation Resistance in KRAS-Mutated Lung Cancer Is Enabled by Stem-like Properties Mediated by an Osteopontin–EGFR Pathway

et al. 2017

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Lung cancers with activating KRAS mutations are characterized by treatment resistance and poor prognosis. In particular, the basis for their resistance to radiation therapy is poorly understood. Here we describe a radiation resistance phenotype conferred by a stem-like subpopulation characterized by mitosis-like condensed chromatin (MLCC), high CD133 expression, invasive potential, and tumor-initiating properties. Mechanistic investigations defined a pathway involving osteopontin and the EGFR in promoting this phenotype. Osteopontin/EGFR-dependent MLCC protected cells against radiation-induced DNA double-strand breaks and repressed putative negative regulators of stem-like properties such as CRMP1 and BIM. The MLCC-positive phenotype defined a subset of KRAS-mutated lung cancers that were enriched for co-occurring genomic alterations in TP53 and CDKN2A. Our results illuminate the basis for the radiation resistance of KRAS-mutated lung cancers with possible implications for prognostic and therapeutic strategies.

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An H3K9/S10 methyl-phospho switch modulates Polycomb and Pol II binding at repressed genes during differentiation

Cited by 35 publications

References 34 publications

Protein kinase Msk1 physically and functionally interacts with the KMT2A/MLL1 methyltransferase complex and contributes to the regulation of multiple target genes

Protein kinase Msk1 physically and functionally interacts with the KMT2A/MLL1 methyltransferase complex and contributes to the regulation of multiple target genes

Three-dimensional genome architecture: players and mechanisms

Radiation Resistance in KRAS-Mutated Lung Cancer Is Enabled by Stem-like Properties Mediated by an Osteopontin–EGFR Pathway

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