XB-ART-52101
Nucleic Acids Res
January 1, 2016;
44
(10):
4703-20.
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A phospho-dependent mechanism involving NCoR and KMT2D controls a permissive chromatin state at Notch target genes.
Oswald F
,
Rodriguez P
,
Giaimo BD
,
Antonello ZA
,
Mira L
,
Mittler G
,
Thiel VN
,
Collins KJ
,
Tabaja N
,
Cizelsky W
,
Rothe M
,
Kühl SJ
,
Kühl M
,
Ferrante F
,
Hein K
,
Kovall RA
,
Dominguez M
,
Borggrefe T
.
Abstract
The transcriptional shift from repression to activation of target genes is crucial for the fidelity of Notch responses through incompletely understood mechanisms that likely involve chromatin-based control. To activate silenced genes, repressive chromatin marks are removed and active marks must be acquired. Histone H3 lysine-4 (H3K4) demethylases are key chromatin modifiers that establish the repressive chromatin state at Notch target genes. However, the counteracting histone methyltransferase required for the active chromatin state remained elusive. Here, we show that the RBP-J interacting factor SHARP is not only able to interact with the NCoR corepressor complex, but also with the H3K4 methyltransferase KMT2D coactivator complex. KMT2D and NCoR compete for the C-terminal SPOC-domain of SHARP. We reveal that the SPOC-domain exclusively binds to phosphorylated NCoR. The balance between NCoR and KMT2D binding is shifted upon mutating the phosphorylation sites of NCoR or upon inhibition of the NCoR kinase CK2β. Furthermore, we show that the homologs of SHARP and KMT2D in Drosophila also physically interact and control Notch-mediated functions in vivo Together, our findings reveal how signaling can fine-tune a committed chromatin state by phosphorylation of a pivotal chromatin-modifier.
PubMed ID: 26912830
PMC ID: PMC4889922
Article link: Nucleic Acids Res
Grant support: [+]
Species referenced: Xenopus laevis
Genes referenced: ash2l cbx3 chd4 cnga1 crebbp cxxc1 dll1 dnmt1 dtx1 gusb hdac1 hes1 hes4 hes5.1 hes5.2 hey1 irf4 kdm6a kmt2a kmt2d kmt2e men1 mmut ncoa6 ncor1 ncor2 notch1 ogt rbbp5 setd5 spen tbca tbl1xr1 tbp tubb2b tubb4b wdr5 wdr82
Article Images: [+] show captions
References [+] :
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A conserved structural motif reveals the essential transcriptional repression function of Spen proteins and their role in developmental signaling.
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Cho, PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex. 2007, Pubmed
Dansithong, RNA steady-state defects in myotonic dystrophy are linked to nuclear exclusion of SHARP. 2011, Pubmed
Dephoure, A quantitative atlas of mitotic phosphorylation. 2008, Pubmed
Di Maira, Protein kinase CK2 phosphorylates and upregulates Akt/PKB. 2005, Pubmed
Doroquez, Split ends antagonizes the Notch and potentiates the EGFR signaling pathways during Drosophila eye development. 2007, Pubmed
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Shi, Sharp, an inducible cofactor that integrates nuclear receptor repression and activation. 2001, Pubmed
Stephens, Whole exome sequencing of adenoid cystic carcinoma. 2013, Pubmed
Tanigaki, Two opposing roles of RBP-J in Notch signaling. 2010, Pubmed
Tsuji, Msx2-interacting nuclear target protein (Mint) deficiency reveals negative regulation of early thymocyte differentiation by Notch/RBP-J signaling. 2007, Pubmed
VanderWielen, Transcriptional repression in the Notch pathway: thermodynamic characterization of CSL-MINT (Msx2-interacting nuclear target protein) complexes. 2011, Pubmed
Wacker, RITA, a novel modulator of Notch signalling, acts via nuclear export of RBP-J. 2011, Pubmed , Xenbase
Wang, Opposing LSD1 complexes function in developmental gene activation and repression programmes. 2007, Pubmed
Wang, Genome-wide analysis reveals conserved and divergent features of Notch1/RBPJ binding in human and murine T-lymphoblastic leukemia cells. 2011, Pubmed
Weng, Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. 2004, Pubmed
Yoo, Nuclear hormone receptor corepressor promotes esophageal cancer cell invasion by transcriptional repression of interferon-γ-inducible protein 10 in a casein kinase 2-dependent manner. 2012, Pubmed
de Boer, Efficient biotinylation and single-step purification of tagged transcription factors in mammalian cells and transgenic mice. 2003, Pubmed
van Nuland, Quantitative dissection and stoichiometry determination of the human SET1/MLL histone methyltransferase complexes. 2013, Pubmed
Aulehla, Oscillating signaling pathways during embryonic development. 2008, Pubmed
Borggrefe, The Notch signaling pathway: transcriptional regulation at Notch target genes. 2009, Pubmed
Borggrefe, Fine-tuning of the intracellular canonical Notch signaling pathway. 2012, Pubmed
Borggrefe, The Notch intracellular domain integrates signals from Wnt, Hedgehog, TGFβ/BMP and hypoxia pathways. 2016, Pubmed
Bray, Notch signalling: a simple pathway becomes complex. 2006, Pubmed
Campos, Histones: annotating chromatin. 2009, Pubmed
Castel, Dynamic binding of RBPJ is determined by Notch signaling status. 2013, Pubmed
Cho, PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex. 2007, Pubmed
Dansithong, RNA steady-state defects in myotonic dystrophy are linked to nuclear exclusion of SHARP. 2011, Pubmed
Dephoure, A quantitative atlas of mitotic phosphorylation. 2008, Pubmed
Di Maira, Protein kinase CK2 phosphorylates and upregulates Akt/PKB. 2005, Pubmed
Doroquez, Split ends antagonizes the Notch and potentiates the EGFR signaling pathways during Drosophila eye development. 2007, Pubmed
Ferres-Marco, Epigenetic silencers and Notch collaborate to promote malignant tumours by Rb silencing. 2006, Pubmed
Guruharsha, The Notch signalling system: recent insights into the complexity of a conserved pathway. 2012, Pubmed
Heck, The transcriptional corepressor SMRTER influences both Notch and ecdysone signaling during Drosophila development. 2012, Pubmed
Hemmati-Brivanlou, Localization of specific mRNAs in Xenopus embryos by whole-mount in situ hybridization. 1992, Pubmed , Xenbase
Herz, The H3K27me3 demethylase dUTX is a suppressor of Notch- and Rb-dependent tumors in Drosophila. 2010, Pubmed
Issaeva, Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth. 2007, Pubmed
Jung, RNA helicase Ddx5 and the noncoding RNA SRA act as coactivators in the Notch signaling pathway. 2013, Pubmed
Kao, A histone deacetylase corepressor complex regulates the Notch signal transduction pathway. 1998, Pubmed , Xenbase
Kopan, The canonical Notch signaling pathway: unfolding the activation mechanism. 2009, Pubmed
Kouzarides, Chromatin modifications and their function. 2007, Pubmed
Krejcí, Notch activation stimulates transient and selective binding of Su(H)/CSL to target enhancers. 2007, Pubmed
Kridel, Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma. 2012, Pubmed
Kuroda, Regulation of marginal zone B cell development by MINT, a suppressor of Notch/RBP-J signaling pathway. 2003, Pubmed
Lee, H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. 2013, Pubmed
Liefke, Histone demethylase KDM5A is an integral part of the core Notch-RBP-J repressor complex. 2010, Pubmed
McHugh, The Xist lncRNA interacts directly with SHARP to silence transcription through HDAC3. 2015, Pubmed
Mikami, Structural insights into the recruitment of SMRT by the corepressor SHARP under phosphorylative regulation. 2014, Pubmed
Mohan, SnapShot: Histone lysine methylase complexes. 2012, Pubmed
Moindrot, A Pooled shRNA Screen Identifies Rbm15, Spen, and Wtap as Factors Required for Xist RNA-Mediated Silencing. 2015, Pubmed
Monfort, Identification of Spen as a Crucial Factor for Xist Function through Forward Genetic Screening in Haploid Embryonic Stem Cells. 2015, Pubmed
Mortensen, MSQuant, an open source platform for mass spectrometry-based quantitative proteomics. 2010, Pubmed
Mulligan, A SIRT1-LSD1 corepressor complex regulates Notch target gene expression and development. 2011, Pubmed
Olsen, Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. 2006, Pubmed
Oswald, RBP-Jkappa/SHARP recruits CtIP/CtBP corepressors to silence Notch target genes. 2005, Pubmed , Xenbase
Oswald, SHARP is a novel component of the Notch/RBP-Jkappa signalling pathway. 2002, Pubmed , Xenbase
Oswald, p300 acts as a transcriptional coactivator for mammalian Notch-1. 2001, Pubmed
Pajerowski, NKAP is a transcriptional repressor of notch signaling and is required for T cell development. 2009, Pubmed
Puente, Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. 2011, Pubmed
Radtke, Notch signaling in the immune system. 2010, Pubmed
Rappsilber, Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. 2007, Pubmed
Rossi, The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development. 2012, Pubmed
Salat, ETO, but not leukemogenic fusion protein AML1/ETO, augments RBP-Jkappa/SHARP-mediated repression of notch target genes. 2008, Pubmed
Shi, Sharp, an inducible cofactor that integrates nuclear receptor repression and activation. 2001, Pubmed
Stephens, Whole exome sequencing of adenoid cystic carcinoma. 2013, Pubmed
Tanigaki, Two opposing roles of RBP-J in Notch signaling. 2010, Pubmed
Tsuji, Msx2-interacting nuclear target protein (Mint) deficiency reveals negative regulation of early thymocyte differentiation by Notch/RBP-J signaling. 2007, Pubmed
VanderWielen, Transcriptional repression in the Notch pathway: thermodynamic characterization of CSL-MINT (Msx2-interacting nuclear target protein) complexes. 2011, Pubmed
Wacker, RITA, a novel modulator of Notch signalling, acts via nuclear export of RBP-J. 2011, Pubmed , Xenbase
Wang, Opposing LSD1 complexes function in developmental gene activation and repression programmes. 2007, Pubmed
Wang, Genome-wide analysis reveals conserved and divergent features of Notch1/RBPJ binding in human and murine T-lymphoblastic leukemia cells. 2011, Pubmed
Weng, Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. 2004, Pubmed
Yoo, Nuclear hormone receptor corepressor promotes esophageal cancer cell invasion by transcriptional repression of interferon-γ-inducible protein 10 in a casein kinase 2-dependent manner. 2012, Pubmed
de Boer, Efficient biotinylation and single-step purification of tagged transcription factors in mammalian cells and transgenic mice. 2003, Pubmed
van Nuland, Quantitative dissection and stoichiometry determination of the human SET1/MLL histone methyltransferase complexes. 2013, Pubmed