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The histone chaperone NAP1L3 is required for haematopoietic stem cell maintenance and differentiation

Nucleosome assembly proteins (NAPs) are histone chaperones with an important role in chromatin structure and epigenetic regulation of gene expression. We find that high gene expression levels of mouse Nap1l3 are restricted to haematopoietic stem cells (HSCs) in mice. Importantly, with shRNA or CRISP...

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Autores principales: Heshmati, Yaser, Kharazi, Shabnam, Türköz, Gözde, Chang, David, Kamali Dolatabadi, Esmat, Boström, Johan, Krstic, Aleksandra, Boukoura, Theodora, Wagner, Emma, Kadri, Nadir, Månsson, Robert, Altun, Mikael, Qian, Hong, Walfridsson, Julian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060140/
https://www.ncbi.nlm.nih.gov/pubmed/30046127
http://dx.doi.org/10.1038/s41598-018-29518-z
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author Heshmati, Yaser
Kharazi, Shabnam
Türköz, Gözde
Chang, David
Kamali Dolatabadi, Esmat
Boström, Johan
Krstic, Aleksandra
Boukoura, Theodora
Wagner, Emma
Kadri, Nadir
Månsson, Robert
Altun, Mikael
Qian, Hong
Walfridsson, Julian
author_facet Heshmati, Yaser
Kharazi, Shabnam
Türköz, Gözde
Chang, David
Kamali Dolatabadi, Esmat
Boström, Johan
Krstic, Aleksandra
Boukoura, Theodora
Wagner, Emma
Kadri, Nadir
Månsson, Robert
Altun, Mikael
Qian, Hong
Walfridsson, Julian
author_sort Heshmati, Yaser
collection PubMed
description Nucleosome assembly proteins (NAPs) are histone chaperones with an important role in chromatin structure and epigenetic regulation of gene expression. We find that high gene expression levels of mouse Nap1l3 are restricted to haematopoietic stem cells (HSCs) in mice. Importantly, with shRNA or CRISPR-Cas9 mediated loss of function of mouse Nap1l3 and with overexpression of the gene, the number of colony-forming cells and myeloid progenitor cells in vitro are reduced. This manifests as a striking decrease in the number of HSCs, which reduces their reconstituting activities in vivo. Downregulation of human NAP1L3 in umbilical cord blood (UCB) HSCs impairs the maintenance and proliferation of HSCs both in vitro and in vivo. NAP1L3 downregulation in UCB HSCs causes an arrest in the G0 phase of cell cycle progression and induces gene expression signatures that significantly correlate with downregulation of gene sets involved in cell cycle regulation, including E2F and MYC target genes. Moreover, we demonstrate that HOXA3 and HOXA5 genes are markedly upregulated when NAP1L3 is suppressed in UCB HSCs. Taken together, our findings establish an important role for NAP1L3 in HSC homeostasis and haematopoietic differentiation.
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spelling pubmed-60601402018-07-31 The histone chaperone NAP1L3 is required for haematopoietic stem cell maintenance and differentiation Heshmati, Yaser Kharazi, Shabnam Türköz, Gözde Chang, David Kamali Dolatabadi, Esmat Boström, Johan Krstic, Aleksandra Boukoura, Theodora Wagner, Emma Kadri, Nadir Månsson, Robert Altun, Mikael Qian, Hong Walfridsson, Julian Sci Rep Article Nucleosome assembly proteins (NAPs) are histone chaperones with an important role in chromatin structure and epigenetic regulation of gene expression. We find that high gene expression levels of mouse Nap1l3 are restricted to haematopoietic stem cells (HSCs) in mice. Importantly, with shRNA or CRISPR-Cas9 mediated loss of function of mouse Nap1l3 and with overexpression of the gene, the number of colony-forming cells and myeloid progenitor cells in vitro are reduced. This manifests as a striking decrease in the number of HSCs, which reduces their reconstituting activities in vivo. Downregulation of human NAP1L3 in umbilical cord blood (UCB) HSCs impairs the maintenance and proliferation of HSCs both in vitro and in vivo. NAP1L3 downregulation in UCB HSCs causes an arrest in the G0 phase of cell cycle progression and induces gene expression signatures that significantly correlate with downregulation of gene sets involved in cell cycle regulation, including E2F and MYC target genes. Moreover, we demonstrate that HOXA3 and HOXA5 genes are markedly upregulated when NAP1L3 is suppressed in UCB HSCs. Taken together, our findings establish an important role for NAP1L3 in HSC homeostasis and haematopoietic differentiation. Nature Publishing Group UK 2018-07-25 /pmc/articles/PMC6060140/ /pubmed/30046127 http://dx.doi.org/10.1038/s41598-018-29518-z Text en © The Author(s) 2018 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
Heshmati, Yaser
Kharazi, Shabnam
Türköz, Gözde
Chang, David
Kamali Dolatabadi, Esmat
Boström, Johan
Krstic, Aleksandra
Boukoura, Theodora
Wagner, Emma
Kadri, Nadir
Månsson, Robert
Altun, Mikael
Qian, Hong
Walfridsson, Julian
The histone chaperone NAP1L3 is required for haematopoietic stem cell maintenance and differentiation
title The histone chaperone NAP1L3 is required for haematopoietic stem cell maintenance and differentiation
title_full The histone chaperone NAP1L3 is required for haematopoietic stem cell maintenance and differentiation
title_fullStr The histone chaperone NAP1L3 is required for haematopoietic stem cell maintenance and differentiation
title_full_unstemmed The histone chaperone NAP1L3 is required for haematopoietic stem cell maintenance and differentiation
title_short The histone chaperone NAP1L3 is required for haematopoietic stem cell maintenance and differentiation
title_sort histone chaperone nap1l3 is required for haematopoietic stem cell maintenance and differentiation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060140/
https://www.ncbi.nlm.nih.gov/pubmed/30046127
http://dx.doi.org/10.1038/s41598-018-29518-z
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