The role of HDAC3 in Notch signal transduction

• Applicant: Professor Dr. Tilman Borggrefe
• Subject Area: Cell Biology ; Biochemistry ; Developmental Biology ; Hematology, Oncology
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 393040308

• Final Report Year: 2023

Final Report Abstract

Aberrant Notch signaling plays a pivotal role in T-cell acute lymphoblastic leukemia (T- ALL) and chronic lymphocytic leukemia (CLL). Amplitude and duration of the Notch response is controlled by ubiquitin-dependent proteasomal degradation of the Notch1 intracellular domain (NICD1), a hallmark of the leukemogenic process. In this project we showed that HDAC3 controls NICD1 acetylation levels directly affecting NICD1 protein stability. Either genetic loss-of-function of HDAC3 or nanomolar concentrations of HDAC inhibitor apicidin lead to downregulation of Notch target genes accompanied by a local reduction of histone acetylation. Importantly, an acetylation-deficient NICD1 mutant is more stable but biologically less active. Collectively, these data show a new HDAC3- and acetylation-dependent mechanism that may be exploited to treat Notch1- dependent leukemias.

Publications

• Histone variant H2A.Z deposition and acetylation directs the canonical Notch signaling response. Nucleic Acids Research, 46(16), 8197-8215.
  Giaimo, Benedetto Daniele; Ferrante, Francesca; Vallejo, Diana M.; Hein, Kerstin; Gutierrez-Perez, Irene; Nist, Andrea; Stiewe, Thorsten; Mittler, Gerhard; Herold, Susanne; Zimmermann, Tobias; Bartkuhn, Marek; Schwarz, Peggy; Oswald, Franz; Dominguez, Maria & Borggrefe, Tilman
  
• Loss of the transcription factor RBPJ induces disease-promoting properties in brain pericytes. Nature Communications, 10(1).
  Diéguez-Hurtado, Rodrigo; Kato, Katsuhiro; Giaimo, Benedetto Daniele; Nieminen-Kelhä, Melina; Arf, Hendrik; Ferrante, Francesca; Bartkuhn, Marek; Zimmermann, Tobias; Bixel, M. Gabriele; Eilken, Hanna M.; Adams, Susanne; Borggrefe, Tilman; Vajkoczy, Peter & Adams, Ralf H.
  
• HDAC3 functions as a positive regulator in Notch signal transduction. Nucleic Acids Research, 48(7), 3496-3512.
  Ferrante, Francesca; Giaimo, Benedetto Daniele; Bartkuhn, Marek; Zimmermann, Tobias; Close, Viola; Mertens, Daniel; Nist, Andrea; Stiewe, Thorsten; Meier-Soelch, Johanna; Kracht, Michael; Just, Steffen; Klöble, Patricia; Oswald, Franz & Borggrefe, Tilman
  
• A Comprehensive Toolbox to Analyze Enhancer–Promoter Functions. Methods in Molecular Biology, 3-22. Springer US.
  Giaimo, Benedetto Daniele; Friedrich, Tobias & Borggrefe, Tilman
  
• Chromatin Regulator SPEN/SHARP in X Inactivation and Disease. Cancers, 13(7), 1665.
  Giaimo, Benedetto; Robert-Finestra, Teresa; Oswald, Franz; Gribnau, Joost & Borggrefe, Tilman
  
• SPEN is required for Xist upregulation during initiation of X chromosome inactivation. Nature Communications, 12(1).
  Robert-Finestra, Teresa; Tan, Beatrice F.; Mira-Bontenbal, Hegias; Timmers, Erika; Gontan, Cristina; Merzouk, Sarra; Giaimo, Benedetto Daniele; Dossin, François; van IJcken Wilfred, F. J.; Martens, John W. M.; Borggrefe, Tilman; Heard, Edith & Gribnau, Joost
  
• SUMOylated non-canonical polycomb PRC1.6 complex as a prerequisite for recruitment of transcription factor RBPJ. Epigenetics & Chromatin, 14(1).
  Sotomska, Małgorzata; Liefke, Robert; Ferrante, Francesca; Schwederski, Heiko; Oswald, Franz & Borggrefe, Tilman
  
• A Drosophila Su(H) model of Adams-Oliver Syndrome reveals cofactor titration as a mechanism underlying developmental defects. PLOS Genetics, 18(8), e1010335.
  Gagliani, Ellen K.; Gutzwiller, Lisa M.; Kuang, Yi; Odaka, Yoshinobu; Hoffmeister, Phillipp; Hauff, Stefanie; Turkiewicz, Aleksandra; Harding-Theobald, Emily; Dolph, Patrick J.; Borggrefe, Tilman; Oswald, Franz; Gebelein, Brian & Kovall, Rhett A.
  
• Endothelial RBPJ Is Essential for the Education of Tumor-Associated Macrophages. Cancer Research, 82(23), 4414-4428.
  Alsina-Sanchis, Elisenda; Mülfarth, Ronja; Moll, Iris; Böhn, Sarah; Wiedmann, Lena; Jordana-Urriza, Lorea; Ziegelbauer, Tara; Zimmer, Eleni; Taylor, Jacqueline; De Angelis, Rigotti Francesca; Stögbauer, Adrian; Giaimo, Benedetto Daniele; Cerwenka, Adelheid; Borggrefe, Tilman; Fischer, Andreas & Rodriguez-Vita, Juan
  
• Enhancer-promoter communication: unraveling enhancer strength and positioning within a given topologically associating domain (TAD). Signal Transduction and Targeted Therapy, 7(1).
  Giaimo, Benedetto Daniele & Borggrefe, Tilman
  
• Hydroxylation of the NOTCH1 intracellular domain regulates Notch signaling dynamics. Cell Death & Disease, 13(7).
  Ferrante, Francesca; Giaimo, Benedetto Daniele; Friedrich, Tobias; Sugino, Toshiya; Mertens, Daniel; Kugler, Sabrina; Gahr, Bernd Martin; Just, Steffen; Pan, Leiling; Bartkuhn, Marek; Potente, Michael; Oswald, Franz & Borggrefe, Tilman
  
• Notch-dependent and -independent functions of transcription factor RBPJ. Nucleic Acids Research, 50(14), 7925-7937.
  Friedrich, Tobias; Ferrante, Francesca; Pioger, Léo; Nist, Andrea; Stiewe, Thorsten; Andrau, Jean-Christophe; Bartkuhn, Marek; Giaimo, Benedetto Daniele & Borggrefe, Tilman
  
• The structure, binding and function of a Notch transcription complex involving RBPJ and the epigenetic reader protein L3MBTL3. Nucleic Acids Research, 50(22), 13083-13099.
  Hall, Daniel; Giaimo, Benedetto Daniele; Park, Sung-Soo; Hemmer, Wiebke; Friedrich, Tobias; Ferrante, Francesca; Bartkuhn, Marek; Yuan, Zhenyu; Oswald, Franz; Borggrefe, Tilman; Rual, Jean-François & Kovall, Rhett A.
  
• The H2A.Z and NuRD associated protein HMG20A controls early head and heart developmental transcription programs. Nature Communications, 14(1).
  Herchenröther, Andreas; Gossen, Stefanie; Friedrich, Tobias; Reim, Alexander; Daus, Nadine; Diegmüller, Felix; Leers, Jörg; Sani, Hakimeh Moghaddas; Gerstner, Sarah; Schwarz, Leah; Stellmacher, Inga; Szymkowiak, Laura Victoria; Nist, Andrea; Stiewe, Thorsten; Borggrefe, Tilman; Mann, Matthias; Mackay, Joel P.; Bartkuhn, Marek; Borchers, Annette ... & Hake, Sandra B.