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Chromatin accessibility promotes hematopoietic and leukemia stem cell activity

Chromatin organization is a highly orchestrated process that influences gene expression, in part by modulating access of regulatory factors to DNA and nucleosomes. Here, we report that the chromatin accessibility regulator HMGN1, a target of recurrent DNA copy gains in leukemia, controls myeloid dif...

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Autores principales: Cabal-Hierro, Lucia, van Galen, Peter, Prado, Miguel A., Higby, Kelly J., Togami, Katsuhiro, Mowery, Cody T., Paulo, Joao A., Xie, Yingtian, Cejas, Paloma, Furusawa, Takashi, Bustin, Michael, Long, Henry W., Sykes, David B., Gygi, Steven P., Finley, Daniel, Bernstein, Bradley E., Lane, Andrew A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076002/
https://www.ncbi.nlm.nih.gov/pubmed/32179749
http://dx.doi.org/10.1038/s41467-020-15221-z
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author Cabal-Hierro, Lucia
van Galen, Peter
Prado, Miguel A.
Higby, Kelly J.
Togami, Katsuhiro
Mowery, Cody T.
Paulo, Joao A.
Xie, Yingtian
Cejas, Paloma
Furusawa, Takashi
Bustin, Michael
Long, Henry W.
Sykes, David B.
Gygi, Steven P.
Finley, Daniel
Bernstein, Bradley E.
Lane, Andrew A.
author_facet Cabal-Hierro, Lucia
van Galen, Peter
Prado, Miguel A.
Higby, Kelly J.
Togami, Katsuhiro
Mowery, Cody T.
Paulo, Joao A.
Xie, Yingtian
Cejas, Paloma
Furusawa, Takashi
Bustin, Michael
Long, Henry W.
Sykes, David B.
Gygi, Steven P.
Finley, Daniel
Bernstein, Bradley E.
Lane, Andrew A.
author_sort Cabal-Hierro, Lucia
collection PubMed
description Chromatin organization is a highly orchestrated process that influences gene expression, in part by modulating access of regulatory factors to DNA and nucleosomes. Here, we report that the chromatin accessibility regulator HMGN1, a target of recurrent DNA copy gains in leukemia, controls myeloid differentiation. HMGN1 amplification is associated with increased accessibility, expression, and histone H3K27 acetylation of loci important for hematopoietic stem cells (HSCs) and leukemia, such as HoxA cluster genes. In vivo, HMGN1 overexpression is linked to decreased quiescence and increased HSC activity in bone marrow transplantation. HMGN1 overexpression also cooperates with the AML-ETO9a fusion oncoprotein to impair myeloid differentiation and enhance leukemia stem cell (LSC) activity. Inhibition of histone acetyltransferases CBP/p300 relieves the HMGN1-associated differentiation block. These data nominate factors that modulate chromatin accessibility as regulators of HSCs and LSCs, and suggest that targeting HMGN1 or its downstream effects on histone acetylation could be therapeutically active in AML.
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spelling pubmed-70760022020-03-18 Chromatin accessibility promotes hematopoietic and leukemia stem cell activity Cabal-Hierro, Lucia van Galen, Peter Prado, Miguel A. Higby, Kelly J. Togami, Katsuhiro Mowery, Cody T. Paulo, Joao A. Xie, Yingtian Cejas, Paloma Furusawa, Takashi Bustin, Michael Long, Henry W. Sykes, David B. Gygi, Steven P. Finley, Daniel Bernstein, Bradley E. Lane, Andrew A. Nat Commun Article Chromatin organization is a highly orchestrated process that influences gene expression, in part by modulating access of regulatory factors to DNA and nucleosomes. Here, we report that the chromatin accessibility regulator HMGN1, a target of recurrent DNA copy gains in leukemia, controls myeloid differentiation. HMGN1 amplification is associated with increased accessibility, expression, and histone H3K27 acetylation of loci important for hematopoietic stem cells (HSCs) and leukemia, such as HoxA cluster genes. In vivo, HMGN1 overexpression is linked to decreased quiescence and increased HSC activity in bone marrow transplantation. HMGN1 overexpression also cooperates with the AML-ETO9a fusion oncoprotein to impair myeloid differentiation and enhance leukemia stem cell (LSC) activity. Inhibition of histone acetyltransferases CBP/p300 relieves the HMGN1-associated differentiation block. These data nominate factors that modulate chromatin accessibility as regulators of HSCs and LSCs, and suggest that targeting HMGN1 or its downstream effects on histone acetylation could be therapeutically active in AML. Nature Publishing Group UK 2020-03-16 /pmc/articles/PMC7076002/ /pubmed/32179749 http://dx.doi.org/10.1038/s41467-020-15221-z Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Cabal-Hierro, Lucia
van Galen, Peter
Prado, Miguel A.
Higby, Kelly J.
Togami, Katsuhiro
Mowery, Cody T.
Paulo, Joao A.
Xie, Yingtian
Cejas, Paloma
Furusawa, Takashi
Bustin, Michael
Long, Henry W.
Sykes, David B.
Gygi, Steven P.
Finley, Daniel
Bernstein, Bradley E.
Lane, Andrew A.
Chromatin accessibility promotes hematopoietic and leukemia stem cell activity
title Chromatin accessibility promotes hematopoietic and leukemia stem cell activity
title_full Chromatin accessibility promotes hematopoietic and leukemia stem cell activity
title_fullStr Chromatin accessibility promotes hematopoietic and leukemia stem cell activity
title_full_unstemmed Chromatin accessibility promotes hematopoietic and leukemia stem cell activity
title_short Chromatin accessibility promotes hematopoietic and leukemia stem cell activity
title_sort chromatin accessibility promotes hematopoietic and leukemia stem cell activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076002/
https://www.ncbi.nlm.nih.gov/pubmed/32179749
http://dx.doi.org/10.1038/s41467-020-15221-z
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