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

Liu, Ting; Kong, Wei-Xia; Tang, Xin; Xu, Man; Wang, Qing-han; Zhang, Bin; Hu, Liangding; Hu, Chen

doi:10.1038/s41419-018-0721-8

Cited by 11 publications

(5 citation statements)

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“…We found that the hiPSCs successfully differentiated into HPCs (Figure 9B), and the group treated with 3,2′-DHF showed significantly increased populations of CD34+ CD45+ cells (Figure 9C). Cell identity of HPCs can be defined by gene regulation networks governed by transcription [59] and several previous studies have shown that various transcription factors regulate HPC differentiation and engraftment [60][61][62]. We investigated whether 3,2′-DHF regulates transcription factors after hiPSC differentiation into HPCs and confirmed that the expression of RUNX1, GATA2, ERG, HOXA9, and CXCR4 were increased in the 3,2′-DHF-treated cells (Figure 9D).…”

supporting

confidence: 54%

3,2′-Dihydroxyflavone Improves the Proliferation and Survival of Human Pluripotent Stem Cells and Their Differentiation into Hematopoietic Progenitor Cells

Kim

Dayem

Gil

et al. 2020

JCM

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Efficient maintenance of the undifferentiated status of human pluripotent stem cells (hiPSCs) is crucial for producing cells with improved proliferation, survival and differentiation, which can be successfully used for stem cell research and therapy. Here, we generated iPSCs from healthy donor peripheral blood mononuclear cells (PBMCs) and analyzed the proliferation and differentiation capacities of the generated iPSCs using single cell NGS-based 24-chromosome aneuploidy screening and RNA sequencing. In addition, we screened various natural compounds for molecules that could enhance the proliferation and differentiation potential of hiPSCs. Among the tested compounds, 3,2′-dihydroxyflavone (3,2′-DHF) significantly increased cell proliferation and expression of naïve stemness markers and decreased the dissociation-induced apoptosis of hiPSCs. Of note, 3,2′-DHF-treated hiPSCs showed upregulation of intracellular glutathione (GSH) and an increase in the percentage of GSH-high cells in an analysis with a FreSHtracer system. Interestingly, culture of the 3,2′-DHF-treated hiPSCs in differentiation media enhanced their mesodermal differentiation and differentiation into CD34+ CD45+ hematopoietic progenitor cells (HPC) and natural killer cells (NK) cells. Taken together, our results demonstrate that the natural compound 3,2′-DHF can improve the proliferation and differentiation capacities of hiPSCs and increase the efficiency of HPC and NK cell production from hiPSCs.

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supporting

confidence: 54%

3,2′-Dihydroxyflavone Improves the Proliferation and Survival of Human Pluripotent Stem Cells and Their Differentiation into Hematopoietic Progenitor Cells

Kim

Dayem

Gil

et al. 2020

JCM

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“…Hematopoietic stem cells (HSCs), which take on the potency to self-renew and differentiate to all lineage blood cells, play an essential role in hematopoiesis ( 39 , 40 ). Studies have shown that ZFP90 can be used as a transcription factor to participate in the regulation of HSC self-renewal and repopulation potential in vivo ( 41 ). Besides, excessive activation of the Wnt/β-catenin signaling pathway, an important signal pathway to participate in SLE ( 42 ), facilitates HSCs to lose the abilities of differentiation ( 43 , 44 ).…”

Section: Discussionmentioning

confidence: 99%

Assessing the Function of the ZFP90 Variant rs1170426 in SLE and the Association Between SLE Drug Target and Susceptibility Genes

et al. 2021

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A genome-wide association study (GWAS) has discovered that a polymorphism in the ZFP90 gene is associated with systemic lupus erythematosus (SLE). In this study, we explored the candidate function of a ZFP90 variant (rs1170426) in the context of SLE and detected the relationship between SLE susceptible genes and SLE drug target genes. First, we investigated the regulatory role of rs1170426 on ZFP90 expression by expression quantitative trait loci (eQTL) analysis in peripheral blood mononuclear cells (PBMCs), T, B, and monocytes cells and annotated the regulatory function of rs1170426 using bioinformatic databases. Second, we compared the case-control difference in ZFP90 expression levels. Third, we analyzed the association of genotype and ZFP90 expression levels with SLE clinical characters. Last, we showed the interaction of SLE susceptibility genes with SLE drug target genes. Subjects with the risk allele “C” of rs1170426 had lower expression levels of ZFP90 in PBMCs (P = 0.006) and CD8+ T cells (P = 0.003) from controls. SLE cases also had lower expression levels compared with controls (P = 2.78E-9). After correction for multiple testing, the ZFP90 expression levels were related to serositis (FDR p = 0.004), arthritis (FDR p = 0.020), hematological involvement (FDR p = 0.021), and increased C-reactive protein (CRP) (FDR p = 0.005) in cases. Furthermore, the SLE susceptible genes and the recognized SLE drug target genes were more likely to act upon each other compared with non-SLE genetic genes (OR = 2.701, P = 1.80E-5). These findings suggest that ZFP90 might play a role in the pathogenesis of SLE, and SLE genetics would contribute to therapeutic drug discovery.

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“…Smarca1 participates in the NURF chromatin remodeling complex, that can limit or promote chromatin accessibility, and thus block or activate gene expression correspondingly 43 . NURF complex has been shown to promote cell proliferation, but a role for this complex in RA is missing 63,64 . Recently, a study reported a role for miR-222 in targeting Brg1, a SWI/SNF chromatin remodeling component, leading to repression of inflammatory cytokine expression in sepsis 28 .…”

Section: Discussionmentioning

confidence: 99%

miR-221/222 drive synovial fibroblast expansion and pathogenesis of TNF-mediated arthritis

Roumelioti

Tzaferis

Konstantopoulos

et al. 2022

Preprint

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MicroRNAs (miRNAs) constitute fine tuners of gene expression and are implicated in a variety of diseases spanning from inflammation to cancer. miRNA expression is deregulated in rheumatoid arthritis (RA), however, their specific role in key arthritogenic cells such as the synovial fibroblast (SF) remains elusive. We have shown in the past that the expression of the miR-221/222 cluster is upregulated in RA SFs. Here, we demonstrate that miR-221/222 activation is downstream of major inflammatory cytokines, such as TNF and IL-1β, which promote miR-221/222 expression independently. miR-221/222 expression in SFs from the huTNFtg mouse model of arthritis correlates with disease progression. Targeted transgenic overexpression of miR-221/222 in SFs of the huTNFtg mouse model led to further expansion of synovial fibroblasts and disease exacerbation. miR-221/222 overexpression altered the transcriptional profile of SFs igniting pathways involved in cell cycle progression and ECM regulation. Validated targets of miR-221/222 included p27 and p57 cell cycle inhibitors, as well as Smarca1 (a chromatin remodeling component). In contrast, complete genetic ablation of miR-221/222 in arthritic mice led to decreased proliferation of fibroblasts, reduced synovial expansion and attenuated disease. scATAC-seq data analysis revealed increased miR-221/222 gene activity in the pathogenic and activated clusters of the intermediate and lining compartment. Taken together, our results establish an SF-specific pathogenic role of the miR-221/222 cluster in arthritis and suggest that its therapeutic targeting in specific subpopulations should inform the design of novel fibroblast-targeted therapies for human disease.

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

Cited by 11 publications

References 50 publications

3,2′-Dihydroxyflavone Improves the Proliferation and Survival of Human Pluripotent Stem Cells and Their Differentiation into Hematopoietic Progenitor Cells

3,2′-Dihydroxyflavone Improves the Proliferation and Survival of Human Pluripotent Stem Cells and Their Differentiation into Hematopoietic Progenitor Cells

Assessing the Function of the ZFP90 Variant rs1170426 in SLE and the Association Between SLE Drug Target and Susceptibility Genes

miR-221/222 drive synovial fibroblast expansion and pathogenesis of TNF-mediated arthritis

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