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  MED12 Regulates HSC-Specific Enhancers Independently of Mediator Kinase Activity to Control Hematopoiesis

Aranda-Orgilles, B., Saldaña-Meyer, R., Wang, E., Trompouki, E., Fassl, A., Lau, S., et al. (2016). MED12 Regulates HSC-Specific Enhancers Independently of Mediator Kinase Activity to Control Hematopoiesis. Cell Stem Cell, 19, 784-799. doi:doi: 10.1016/j.stem.2016.08.004.

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Aranda-Orgilles, Beatriz1, Author
Saldaña-Meyer, Ricardo2, Author
Wang, Eric1, Author
Trompouki, Eirini3, Author              
Fassl, Anne4, Author
Lau, Stephanie1, Author
Mullenders, Jasper1, Author
Rocha, Pedro P.5, Author
Raviram, Ramya5, Author
Guillamot, María1, Author
Sánchez-Díaz, María1, Author
Wang, Kun1, Author
Kayembe, Clarisse1, Author
Zhang, Nan1, Author
Amoasii, Leonela6, Author
Choudhuri, Avik7, Author
Skok, Jane A.5, Author
Schober, Markus8, Author
Reinberg, Danny2, Author
Sicinski, Piotr4, Author
Schrewe, Heinrich9, AuthorTsirigos, Aristotelis1, 10, AuthorZon, Leonard I.7, AuthorAifantis, Iannis1, Author more..
Affiliations:
1Dept. of Pathology, Laura & Issac Perlmutter Cancer Center, and The Helen L. and Martin s. Kimmel Center for Stem Cell Biology, NYU School of Medicine , New York, USA, ou_persistent22              
2Howard Hughes Medical Institute and Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, USA, ou_persistent22              
3Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, 79108 Freiburg, DE, ou_2243640              
4Department of Cancer Biology, Dana-Farber Cancer Instititute, and Department of Genetics, Harvard Medical School of Medicine, Boston, USA, ou_persistent22              
5Department of Pathology, NYU School of Medicine, New York, USA, ou_persistent22              
6Department of Molecular Biology, The University of Texas Southwestern medical Center, Dallas, Texas, USA, ou_persistent22              
7Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Harvard medical School and Howard Hughes Medical Institute, Boston, USA, ou_persistent22              
8The 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, USA, ou_persistent22              
9Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany, ou_persistent22              
10Center for Health Informatics and Bioinformatics, NYU School of medicine, New York, USA, ou_persistent22              

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 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.

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Language(s): eng - English
 Dates: 2016-12-01
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: doi: 10.1016/j.stem.2016.08.004
 Degree: -

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Title: Cell Stem Cell
Source Genre: Journal
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Publ. Info: Cambridge, Mass. : Cell Press
Pages: - Volume / Issue: 19 Sequence Number: - Start / End Page: 784 - 799 Identifier: ISSN: 1934-5909
CoNE: https://pure.mpg.de/cone/journals/resource/1934-5909