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The transcription factor Zfp90 regulates the self-renewal and differentiation of hematopoietic stem cells.

ABSTRACT: Hematopoietic stem cells (HSCs) can give rise to all blood cells that are essential to defend against pathogen invasion. The defective capability of HSC self-renewal is linked to many serious diseases, such as anemia. However, the potential mechanism regulating HSC self-renewal has not been thoroughly elucidated to date. In this study, we showed that Zfp90 was highly expressed in HSCs. Zfp90 deficiency in the hematopoietic system caused impaired HSPC pools and led to HSC dysfunction. We showed that Zfp90 deletion inhibited HSC proliferation, while HSC apoptosis was not affected. Regarding the mechanism of this effect on HSC proliferation, we found that Zfp90 interacted with Snf2l, a subunit of the NURF complex, to regulate Hoxa9 expression. Ectopic expression of Hoxa9 rescued the HSC repopulation capacity in Zfp90-deficient mice, which indicates that Hoxa9 is the downstream effector of Zfp90. In summary, our findings identify Zfp90 as a key transcription factor in determining the fate of HSCs.

SUBMITTER: Liu T

PROVIDER: S-EPMC5992204 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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The transcription factor Zfp90 regulates the self-renewal and differentiation of hematopoietic stem cells.

Liu Ting T Kong Wei-Xia WX Tang Xiao-Yi XY Xu Man M Wang Qing-Han QH Zhang Bin B Hu Liang-Ding LD Chen Hu H

Cell death & disease 20180607 6

Hematopoietic stem cells (HSCs) can give rise to all blood cells that are essential to defend against pathogen invasion. The defective capability of HSC self-renewal is linked to many serious diseases, such as anemia. However, the potential mechanism regulating HSC self-renewal has not been thoroughly elucidated to date. In this study, we showed that Zfp90 was highly expressed in HSCs. Zfp90 deficiency in the hematopoietic system caused impaired HSPC pools and led to HSC dysfunction. We showed t ...[more]

PMID: 29880802

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Project description:BackgroundThioredoxin-1 (TXN1) is one of the major cellular antioxidants in mammals and is involved in a wide range of physiological cellular responses. However, little is known about the roles and the underlying molecular mechanisms of TXN1 in the regulation of hematopoietic stem/progenitor cells (HSPCs).MethodsTXN1 conditional knockout mice (ROSA-CreER-TXN1fl/fl) and TXN1fl/fl control mice were used. The mice were treated with tamoxifen and the number and biological functions of HSPCs were measured by flow cytometry, PCR and western blot. Limiting dilution competitive transplantation with sorted HSCs and serial transplantations were performed to assess the effects of TXN1 knockout on HSC self-renewal and long-term reconstitutional capacity. RNA sequencing (RNA-seq) was performed to investigate the downstream molecular pathways of TXN1 deletion in murine HSPCs. CRISPR/Cas9 knockout experiments were performed in vitro in EML murine hematopoietic stem/progenitor cell line to investigate the effects of TXN1 and/or TP53 deletion on cell survival, senescence and colony forming units. TP53 protein degradation assay, CHiP PCR and PGL3 firefly/renilla reporter assay were performed. The effects of TXN1 on various molecular pathways relevant to HSC radiation protection were examined in vitro and in vivo.ResultsTXN1-TP53 tumor suppressor axis regulates HSPC biological fitness. Deletion of TXN1 in HSPCs using in vivo and in vitro models activates TP53 signaling pathway, and attenuates HSPC capacity to reconstitute hematopoiesis. Furthermore, we found that knocking out of TXN1 renders HSPCs more sensitive to radiation and treatment with recombinant TXN1 promotes the proliferation and expansion of HSPCs.ConclusionsOur findings suggest that TXN1-TP53 axis acts as a regulatory mechanism in HSPC biological functions. Additionally, our study demonstrates the clinical potential of TXN1 for enhancing hematopoietic recovery in hematopoietic stem cell transplant and protecting HSPCs from radiation injury.

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The transcription factor Zfp90 regulates the self-renewal and differentiation of hematopoietic stem cells.

Publications

The transcription factor Zfp90 regulates the self-renewal and differentiation of hematopoietic stem cells.

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