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Transcriptomic and Epigenomic Profiling of Histone Deacetylase Inhibitor Treatment Reveals Distinct Gene Regulation Profiles Leading to Impaired Neutrophil Development

The clinical use of histone deacetylase inhibitors (HDACi) for the treatment of bone marrow failure and hematopoietic malignancies has increased dramatically over the last decades. Nonetheless, their effects on normal myelopoiesis remain poorly evaluated. Here, we treated cord blood derived CD34+ pr...

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Autores principales: Govers, Anita M.A.P., Wiggers, Caroline R.M., van Boxtel, Ruben, Mokry, Michal, Nieuwenhuis, Edward E.S., Creyghton, Menno P., Bartels, Marije, Coffer, Paul J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Wolters Kluwer Health 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745919/
https://www.ncbi.nlm.nih.gov/pubmed/31723844
http://dx.doi.org/10.1097/HS9.0000000000000270
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author Govers, Anita M.A.P.
Wiggers, Caroline R.M.
van Boxtel, Ruben
Mokry, Michal
Nieuwenhuis, Edward E.S.
Creyghton, Menno P.
Bartels, Marije
Coffer, Paul J.
author_facet Govers, Anita M.A.P.
Wiggers, Caroline R.M.
van Boxtel, Ruben
Mokry, Michal
Nieuwenhuis, Edward E.S.
Creyghton, Menno P.
Bartels, Marije
Coffer, Paul J.
author_sort Govers, Anita M.A.P.
collection PubMed
description The clinical use of histone deacetylase inhibitors (HDACi) for the treatment of bone marrow failure and hematopoietic malignancies has increased dramatically over the last decades. Nonetheless, their effects on normal myelopoiesis remain poorly evaluated. Here, we treated cord blood derived CD34+ progenitor cells with two chemically distinct HDACi inhibitors MS-275 or SAHA and analyzed their effects on the transcriptome (RNA-seq), epigenome (H3K27ac ChIP-seq) and functional and morphological characteristics during neutrophil development. MS-275 (entinostat) selectively inhibits class I HDACs, with a preference for HDAC1, while SAHA (vorinostat) is a non-selective class I/II HDACi. Treatment with individual HDACi resulted in both overlapping and distinct effects on both transcriptome and epigenome, whereas functional effects were relatively similar. Both HDACi resulted in reduced expansion and increased apoptosis in neutrophil progenitor cells. Morphologically, HDACi disrupted normal neutrophil differentiation what was illustrated by decreased percentages of mature neutrophils. In addition, while SAHA treatment clearly showed a block at the promyelocytic stage, MS-275 treatment was characterized by dysplastic features and skewing towards the monocytic lineage. These effects could be mimicked using shRNA-mediated knockdown of HDAC1. Taken together, our data provide novel insights into the effects of HDAC inhibition on normal hematopoietic cells during neutrophil differentiation. These findings should be taken into account when considering the clinical use of MS-275 and SAHA, and can be potentially utilized to tailor more specific, hematopoietic-directed HDACi in the future.
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spelling pubmed-67459192019-11-13 Transcriptomic and Epigenomic Profiling of Histone Deacetylase Inhibitor Treatment Reveals Distinct Gene Regulation Profiles Leading to Impaired Neutrophil Development Govers, Anita M.A.P. Wiggers, Caroline R.M. van Boxtel, Ruben Mokry, Michal Nieuwenhuis, Edward E.S. Creyghton, Menno P. Bartels, Marije Coffer, Paul J. Hemasphere Article The clinical use of histone deacetylase inhibitors (HDACi) for the treatment of bone marrow failure and hematopoietic malignancies has increased dramatically over the last decades. Nonetheless, their effects on normal myelopoiesis remain poorly evaluated. Here, we treated cord blood derived CD34+ progenitor cells with two chemically distinct HDACi inhibitors MS-275 or SAHA and analyzed their effects on the transcriptome (RNA-seq), epigenome (H3K27ac ChIP-seq) and functional and morphological characteristics during neutrophil development. MS-275 (entinostat) selectively inhibits class I HDACs, with a preference for HDAC1, while SAHA (vorinostat) is a non-selective class I/II HDACi. Treatment with individual HDACi resulted in both overlapping and distinct effects on both transcriptome and epigenome, whereas functional effects were relatively similar. Both HDACi resulted in reduced expansion and increased apoptosis in neutrophil progenitor cells. Morphologically, HDACi disrupted normal neutrophil differentiation what was illustrated by decreased percentages of mature neutrophils. In addition, while SAHA treatment clearly showed a block at the promyelocytic stage, MS-275 treatment was characterized by dysplastic features and skewing towards the monocytic lineage. These effects could be mimicked using shRNA-mediated knockdown of HDAC1. Taken together, our data provide novel insights into the effects of HDAC inhibition on normal hematopoietic cells during neutrophil differentiation. These findings should be taken into account when considering the clinical use of MS-275 and SAHA, and can be potentially utilized to tailor more specific, hematopoietic-directed HDACi in the future. Wolters Kluwer Health 2019-08-01 /pmc/articles/PMC6745919/ /pubmed/31723844 http://dx.doi.org/10.1097/HS9.0000000000000270 Text en Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association. http://creativecommons.org/licenses/by-nc-nd/4.0 This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0
spellingShingle Article
Govers, Anita M.A.P.
Wiggers, Caroline R.M.
van Boxtel, Ruben
Mokry, Michal
Nieuwenhuis, Edward E.S.
Creyghton, Menno P.
Bartels, Marije
Coffer, Paul J.
Transcriptomic and Epigenomic Profiling of Histone Deacetylase Inhibitor Treatment Reveals Distinct Gene Regulation Profiles Leading to Impaired Neutrophil Development
title Transcriptomic and Epigenomic Profiling of Histone Deacetylase Inhibitor Treatment Reveals Distinct Gene Regulation Profiles Leading to Impaired Neutrophil Development
title_full Transcriptomic and Epigenomic Profiling of Histone Deacetylase Inhibitor Treatment Reveals Distinct Gene Regulation Profiles Leading to Impaired Neutrophil Development
title_fullStr Transcriptomic and Epigenomic Profiling of Histone Deacetylase Inhibitor Treatment Reveals Distinct Gene Regulation Profiles Leading to Impaired Neutrophil Development
title_full_unstemmed Transcriptomic and Epigenomic Profiling of Histone Deacetylase Inhibitor Treatment Reveals Distinct Gene Regulation Profiles Leading to Impaired Neutrophil Development
title_short Transcriptomic and Epigenomic Profiling of Histone Deacetylase Inhibitor Treatment Reveals Distinct Gene Regulation Profiles Leading to Impaired Neutrophil Development
title_sort transcriptomic and epigenomic profiling of histone deacetylase inhibitor treatment reveals distinct gene regulation profiles leading to impaired neutrophil development
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745919/
https://www.ncbi.nlm.nih.gov/pubmed/31723844
http://dx.doi.org/10.1097/HS9.0000000000000270
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