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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Bibliographic Details
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 Nature Publishing Group Nature Portfolio
Subjects:	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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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/s41598-018-29518-z