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

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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Published in:Scientific reports Vol. 8; no. 1; pp. 11202 - 17
Main Authors: 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
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 25-07-2018
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Subjects:
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Animals
Cell cycle
Cell Cycle Checkpoints - genetics
Cell Differentiation - genetics
Cell Proliferation - genetics
Chaperones
Chromatin
Colony-forming cells
Cord blood
CRISPR
E2F protein
Fetal Blood - metabolism
Gene expression
Gene Expression Regulation, Developmental - genetics
Hematopoietic stem cells
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - metabolism
Histone Chaperones - genetics
Homeodomain Proteins - genetics
Homeostasis
Humanities and Social Sciences
Humans
Medicin och hälsovetenskap
Mice
multidisciplinary
Myc protein
Nerve Tissue Proteins - genetics
Progenitor cells
Resting Phase, Cell Cycle - genetics
Science
Science (multidisciplinary)
Stem cell transplantation
Stem cells
Umbilical cord
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Abstract 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.
AbstractList Abstract 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.
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.
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.
ArticleNumber 11202
Author Kamali Dolatabadi, Esmat
Månsson, Robert
Altun, Mikael
Krstic, Aleksandra
Qian, Hong
Walfridsson, Julian
Türköz, Gözde
Boukoura, Theodora
Kharazi, Shabnam
Boström, Johan
Heshmati, Yaser
Chang, David
Wagner, Emma
Kadri, Nadir
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  organization: Center for Haematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital
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  doi: 10.1016/S0006-291X(03)00907-0
  contributor:
    fullname: K Ohkuni
– volume: 27
  start-page: 6093
  year: 2007
  ident: 29518_CR52
  publication-title: Mol Cell Biol
  doi: 10.1128/MCB.00789-07
  contributor:
    fullname: M Attia
– volume: 1783
  start-page: 1595
  year: 2008
  ident: 29518_CR63
  publication-title: Biochimica et biophysica acta
  doi: 10.1016/j.bbamcr.2008.03.019
  contributor:
    fullname: M Grande
SSID ssj0000529419
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Snippet Nucleosome assembly proteins (NAPs) are histone chaperones with an important role in chromatin structure and epigenetic regulation of gene expression. We find...
Abstract Nucleosome assembly proteins (NAPs) are histone chaperones with an important role in chromatin structure and epigenetic regulation of gene expression....
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SubjectTerms 13/100
13/106
13/2
13/89
42/41
45/77
631/154/555
631/67/1990/283/1897
64/60
Animals
Cell cycle
Cell Cycle Checkpoints - genetics
Cell Differentiation - genetics
Cell Proliferation - genetics
Chaperones
Chromatin
Colony-forming cells
Cord blood
CRISPR
E2F protein
Fetal Blood - metabolism
Gene expression
Gene Expression Regulation, Developmental - genetics
Hematopoietic stem cells
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - metabolism
Histone Chaperones - genetics
Homeodomain Proteins - genetics
Homeostasis
Humanities and Social Sciences
Humans
Medicin och hälsovetenskap
Mice
multidisciplinary
Myc protein
Nerve Tissue Proteins - genetics
Progenitor cells
Resting Phase, Cell Cycle - genetics
Science
Science (multidisciplinary)
Stem cell transplantation
Stem cells
Umbilical cord
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Title The histone chaperone NAP1L3 is required for haematopoietic stem cell maintenance and differentiation
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