title: PADI4 acts as a coactivator of Tal1 by counteracting repressive histone arginine methylation.
abstract: The transcription factor Tal1 is a critical activator or repressor of gene expression in hematopoiesis and leukaemia. The mechanism by which Tal1 differentially influences transcription of distinct genes is not fully understood. Here we show that Tal1 interacts with the peptidylarginine deiminase IV (PADI4). We demonstrate that PADI4 can act as an epigenetic coactivator through influencing H3R2me2a. At the Tal1/PADI4 target gene IL6ST the repressive H3R2me2a mark triggered by PRMT6 is counteracted by PADI4, which augments the active H3K4me3 mark and thus increases IL6ST expression. In contrast, at the CTCF promoter PADI4 acts as a repressor. We propose that the influence of PADI4 on IL6ST transcription plays a role in the control of IL6ST expression during lineage differentiation of hematopoietic stem/progenitor cells. These results open the possibility to pharmacologically influence Tal1 in leukaemia.
authors.affiliation: Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Paul-Ehrlich-Strasse 42-44, D-60596 Frankfurt am Main, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Kolodziej
authors.affiliation: Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Paul-Ehrlich-Strasse 42-44, D-60596 Frankfurt am Main, Germany.
authors.forename: Olga N
authors.initials: ON
authors.lastname: Kuvardina
authors.affiliation: Department of Medicine, Hematology/Oncology, Johann-Wolfgang-Goethe University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Oellerich
authors.affiliation: 1] Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Paul-Ehrlich-Strasse 42-44, D-60596 Frankfurt am Main, Germany [2].
authors.forename: Julia
authors.initials: J
authors.lastname: Herglotz
authors.affiliation: 1] Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Paul-Ehrlich-Strasse 42-44, D-60596 Frankfurt am Main, Germany [2].
authors.forename: Ingo
authors.initials: I
authors.lastname: Backert
authors.affiliation: Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Paul-Ehrlich-Strasse 42-44, D-60596 Frankfurt am Main, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Kohrs
authors.affiliation: Institute of Pharmaceutical Chemistry, Johann-Wolfgang-Goethe University, Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Estel la
authors.initials: El
authors.lastname: Buscató
authors.affiliation: Institute of Pharmaceutical Chemistry, Johann-Wolfgang-Goethe University, Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Wittmann
authors.affiliation: Medical-University Goettingen, Transcriptome Analysis Laboratory, Justus-von-Liebig-Weg 11, D-37077 Goettingen, Germany.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Salinas-Riester
authors.affiliation: German Red Cross Blood Service and Institute for Transfusion Medicine and Immunohematology, Johann-Wolfgang-Goethe University, Sandhofstrasse 1, D-60528 Frankfurt am Main, Germany.
authors.forename: Halvard
authors.initials: H
authors.lastname: Bonig
authors.affiliation: Institute of Pharmaceutical Chemistry, Johann-Wolfgang-Goethe University, Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Karas
authors.affiliation: 1] Department of Medicine, Hematology/Oncology, Johann-Wolfgang-Goethe University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany [2] German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Serve
authors.affiliation: 1] Institute of Pharmaceutical Chemistry, Johann-Wolfgang-Goethe University, Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany [2] German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Ewgenij
authors.initials: E
authors.lastname: Proschak
authors.affiliation: Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Paul-Ehrlich-Strasse 42-44, D-60596 Frankfurt am Main, Germany.
authors.forename: Jörn
authors.initials: J
authors.lastname: Lausen
mesh_terms: D001120:Arginine / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D000076246:CCCTC-Binding Factor; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D050822:Cytokine Receptor gp130 / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006867:Hydrolases / Q000235:genetics* / Q000378:metabolism; D008745:Methylation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1
chemical_list: D001120:Arginine; D051792:Basic Helix-Loop-Helix Proteins; D000076246:CCCTC-Binding Factor; D050822:Cytokine Receptor gp130; D006657:Histones; D006867:Hydrolases; D009687:Nuclear Proteins; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D011484:Protein-Arginine N-Methyltransferases; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C000619697:CTCF protein, human; C494199:IL6ST protein, human; C067143:TAL1 protein, human; C447833:PRMT6 protein, human; C000629235:PADI4 protein, human