title: MED12 Regulates HSC-Specific Enhancers Independently of Mediator Kinase Activity to Control Hematopoiesis.
abstract: Hematopoietic-specific transcription factors require coactivators to communicate with the general transcription machinery and establish transcriptional programs that maintain hematopoietic stem cell (HSC) self-renewal, promote differentiation, and prevent malignant transformation. Mediator is a large coactivator complex that bridges enhancer-localized transcription factors with promoters, but little is known about Mediator function in adult stem cell self-renewal and differentiation. We show that MED12, a member of the Mediator kinase module, is an essential regulator of HSC homeostasis, as in vivo deletion of Med12 causes rapid bone marrow aplasia leading to acute lethality. Deleting other members of the Mediator kinase module does not affect HSC function, suggesting kinase-independent roles of MED12. MED12 deletion destabilizes P300 binding at lineage-specific enhancers, resulting in H3K27Ac depletion, enhancer de-activation, and consequent loss of HSC stemness signatures. As MED12 mutations have been described recently in blood malignancies, alterations in MED12-dependent enhancer regulation may control both physiological and malignant hematopoiesis.
authors: Department of Pathology, Laura & Isaac Perlmutter Cancer Center, and The Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA.
authors: Beatriz
authors: B
authors: Aranda-Orgilles
authors: Howard Hughes Medical Institute and Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY 10016, USA.
authors: Ricardo
authors: R
authors: Saldaña-Meyer
authors: Department of Pathology, Laura & Isaac Perlmutter Cancer Center, and The Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA.
authors: Eric
authors: E
authors: Wang
authors: Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
authors: Eirini
authors: E
authors: Trompouki
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors: Anne
authors: A
authors: Fassl
authors: Department of Pathology, Laura & Isaac Perlmutter Cancer Center, and The Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA.
authors: Stephanie
authors: S
authors: Lau
authors: Department of Pathology, Laura & Isaac Perlmutter Cancer Center, and The Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA.
authors: Jasper
authors: J
authors: Mullenders
authors: Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.
authors: Pedro P
authors: PP
authors: Rocha
authors: Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.
authors: Ramya
authors: R
authors: Raviram
authors: Department of Pathology, Laura & Isaac Perlmutter Cancer Center, and The Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA.
authors: María
authors: M
authors: Guillamot
authors: Department of Pathology, Laura & Isaac Perlmutter Cancer Center, and The Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA.
authors: María
authors: M
authors: Sánchez-Díaz
authors: Department of Pathology, Laura & Isaac Perlmutter Cancer Center, and The Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA.
authors: Kun
authors: K
authors: Wang
authors: Department of Pathology, Laura & Isaac Perlmutter Cancer Center, and The Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA.
authors: Clarisse
authors: C
authors: Kayembe
authors: Department of Pathology, Laura & Isaac Perlmutter Cancer Center, and The Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA.
authors: Nan
authors: N
authors: Zhang
authors: Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
authors: Leonela
authors: L
authors: Amoasii
authors: Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115, USA.
authors: Avik
authors: A
authors: Choudhuri
authors: Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.
authors: Jane A
authors: JA
authors: Skok
authors: The Ronald O. Perelman Department of Dermatology and Department of Cell Biology, The Helen L. and Martin S. Kimmel Center for Stem Cell Biology, Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA.
authors: Markus
authors: M
authors: Schober
authors: Howard Hughes Medical Institute and Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY 10016, USA.
authors: Danny
authors: D
authors: Reinberg
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors: Piotr
authors: P
authors: Sicinski
authors: Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors: Heinrich
authors: H
authors: Schrewe
authors: Department of Pathology, Laura & Isaac Perlmutter Cancer Center, and The Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA; Center for Health Informatics and Bioinformatics, NYU School of Medicine, New York, NY 10016, USA.
authors: Aristotelis
authors: A
authors: Tsirigos
authors: Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115, USA.
authors: Leonard I
authors: LI
authors: Zon
authors: Department of Pathology, Laura & Isaac Perlmutter Cancer Center, and The Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA. Electronic address: iannis.aifantis@nyumc.org.
authors: Iannis
authors: I
authors: Aifantis
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001853:Bone Marrow / Q000473:pathology; D002470:Cell Survival / Q000235:genetics; D002843:Chromatin / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D017353:Gene Deletion; D020869:Gene Expression Profiling; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D056892:Mediator Complex / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D002843:Chromatin; D056892:Mediator Complex; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C539582:Med12 protein, mouse