Publications by authors named "Shanhe Yu"

8 Publications

  • Page 1 of 1

IRF8 Impacts Self-Renewal of Hematopoietic Stem Cells by Regulating TLR9 Signaling Pathway of Innate Immune Cells.

Adv Sci (Weinh) 2021 Aug 8:e2101031. Epub 2021 Aug 8.

Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine, International Center for Aging and Cancer, Collaborative Innovation Center of Hematology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200025, China.

IRF8 is a key regulator of innate immunity receptor signaling and plays diverse functions in the development of hematopoietic cells. The effects of IRF8 on hematopoietic stem cells (HSCs) are still unknown. Here, it is demonstrated that IRF8 deficiency results in a decreased number of long-term HSCs (LT-HSCs) in mice. However, the repopulation capacity of individual HSCs is significantly increased. Transcriptomic analysis shows that IFN-γ and IFN-α signaling is downregulated in IRF8-deficient HSCs, while their response to proinflammatory cytokines is unchanged ex vivo. Further tests show that Irf8 HSCs can not respond to CpG, an agonist of Toll-like receptor 9 (TLR9) in mice, while long-term CpG stimulation increases wild-type HSC abundance and decreases their bone marrow colony-forming capacity. Mechanistically, as the primary producer of proinflammatory cytokines in response to CpG stimulation, dendritic cells has a blocked TLR9 signaling due to developmental defect in Irf8 mice. Macrophages remain functionally intact but severely reduce in Irf8 mice. In NK cells, IRF8 directly regulates the expression of Tlr9 and its deficiency leads to no increased IFNγ production upon CpG stimulation. These results indicate that IRF8 regulates HSCs, at least in part, through controlling TLR9 signaling in diverse innate immune cells.
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http://dx.doi.org/10.1002/advs.202101031DOI Listing
August 2021

IRF4 and IRF8 expression are associated with clinical phenotype and clinico-hematological response to hydroxyurea in essential thrombocythemia.

Front Med 2021 Jul 31. Epub 2021 Jul 31.

Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, Collaborative Innovation Center of Hematology, National Research Center for translational Medicine (Shanghai), Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.

The morbidity and mortality of myeloproliferative neoplasms (MPNs) are primarily caused by arterial and venous complications, progression to myelofibrosis, and transformation to acute leukemia. However, identifying molecular-based biomarkers for risk stratification of patients with MPNs remains a challenge. We have previously shown that interferon regulatory factor-8 (IRF8) and IRF4 serve as tumor suppressors in myeloid cells. In this study, we evaluated the expression of IRF4 and IRF8 and the JAK2V617F mutant allele burden in patients with MPNs. Patients with decreased IRF4 expression were correlated with a more developed MPN phenotype in myelofibrosis (MF) and secondary AML (sAML) transformed from MPNs versus essential thrombocythemia (ET). Negative correlations between the JAK2V617F allele burden and the expression of IRF8 (P < 0.05) and IRF4 (P < 0.001) and between white blood cell (WBC) count and IRF4 expression (P < 0.05) were found in ET patients. IRF8 expression was negatively correlated with the JAK2V617F allele burden (P < 0.05) in polycythemia vera patients. Complete response (CR), partial response (PR), and no response (NR) were observed in 67.5%,10%, and 22.5% of ET patients treated with hydroxyurea (HU), respectively, in 12 months. At 3 months, patients in the CR group showed high IRF4 and IRF8 expression compared with patients in the PR and NR groups. In the 12-month therapy period, low IRF4 and IRF8 expression were independently associated with the unfavorable response to HU and high WBC count. Our data indicate that the expression of IRF4 and IRF8 was associated with the MPN phenotype, which may serve as biomarkers for the response to HU in ET.
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http://dx.doi.org/10.1007/s11684-021-0858-1DOI Listing
July 2021

3,3',5-Triiodothyroacetic acid (TRIAC) induces embryonic ζ-globin expression via thyroid hormone receptor α.

J Hematol Oncol 2021 06 26;14(1):99. Epub 2021 Jun 26.

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

The human ζ-globin gene (HBZ) is transcribed in primitive erythroid cells only during the embryonic stages of development. Reactivation of this embryonic globin synthesis would likely alleviate symptoms both in α-thalassemia and sickle-cell disease. However, the molecular mechanisms controlling ζ-globin expression have remained largely undefined. Moreover, the pharmacologic agent capable of inducing ζ-globin production is currently unavailable. Here, we show that TRIAC, a bioactive thyroid hormone metabolite, significantly induced ζ-globin gene expression during zebrafish embryogenesis. The induction of ζ-globin expression by TRIAC was also observed in human K562 erythroleukemia cell line and primary erythroid cells. Thyroid hormone receptor α (THRA) deficiency abolished the ζ-globin-inducing effect of TRIAC. Furthermore, THRA could directly bind to the distal enhancer regulatory element to regulate ζ-globin expression. Our study provides the first evidence that TRIAC acts as a potent inducer of ζ-globin expression, which might serve as a new potential therapeutic option for patients with severe α-thalassemia or sickle-cell disease.
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http://dx.doi.org/10.1186/s13045-021-01108-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235803PMC
June 2021

CytoTree: an R/Bioconductor package for analysis and visualization of flow and mass cytometry data.

BMC Bioinformatics 2021 Mar 22;22(1):138. Epub 2021 Mar 22.

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 197 Ruijin Er Road, Shanghai, 200025, China.

Background: The rapidly increasing dimensionality and throughput of flow and mass cytometry data necessitate new bioinformatics tools for analysis and interpretation, and the recently emerging single-cell-based algorithms provide a powerful strategy to meet this challenge.

Results: Here, we present CytoTree, an R/Bioconductor package designed to analyze and interpret multidimensional flow and mass cytometry data. CytoTree provides multiple computational functionalities that integrate most of the commonly used techniques in unsupervised clustering and dimensionality reduction and, more importantly, support the construction of a tree-shaped trajectory based on the minimum spanning tree algorithm. A graph-based algorithm is also implemented to estimate the pseudotime and infer intermediate-state cells. We apply CytoTree to several examples of mass cytometry and time-course flow cytometry data on heterogeneity-based cytology and differentiation/reprogramming experiments to illustrate the practical utility achieved in a fast and convenient manner.

Conclusions: CytoTree represents a versatile tool for analyzing multidimensional flow and mass cytometry data and to producing heuristic results for trajectory construction and pseudotime estimation in an integrated workflow.
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http://dx.doi.org/10.1186/s12859-021-04054-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983272PMC
March 2021

Glucagon-like peptide-1 receptor expression and its functions are regulated by androgen.

Biomed Pharmacother 2019 Dec 24;120:109555. Epub 2019 Oct 24.

Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai 200025, China. Electronic address:

Glucagon-like peptide-1 receptor (GLP-1R) is an important pharmacological target for type 2 diabetes mellitus because it maintains glucose homeostasis and promotes β cell proliferation. Androgen is suggested not only to regulate hypothalamic-pituitary-gonadal axis but also to affect metabolism. In this study, Glp1r mRNA was found widely expressed in normal male mice and its levels were positively correlated with the serum testosterone (T) concentrations. Using mouse insulinoma 6 (MIN6) cells, which highly express GLP-1R, we observed GLP-1R was upregulated both at transcriptional and protein levels induced by dihydrotestosterone (DHT) and was downregulated by androgen receptor inhibitor ARN-509 or small interfering RNA (siRNA) targeting Glp1r mRNA. In normal C57BL/6 mice and db/db mice, Glp1r mRNA levels in the pancreases increased in the DHT treatment group and decreased in the ARN-509 treatment group. And the increased GLP-1R expression had insulinotropic function both in vitro and in vivo. Further analysis showed that the androgen receptor (Ar) located in the cytosol of MIN6 cells and translocated to the nucleus after DHT treatment. In addition, we found that there was an Ar motif in the promoter region of the Glp1r gene. Further studies revealed that the translocated DHT/Ar complex from the cytosol to the nucleus bound to the Ar motif of the Glp1r gene and upregulated gene transcription. Taken together, the widely expressed GLP-1R was positively regulated by androgen under physiological condition and in diabetic models at the transcriptional level.
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http://dx.doi.org/10.1016/j.biopha.2019.109555DOI Listing
December 2019

Retinoic acid inducible gene-I slows down cellular senescence through negatively regulating the integrin β3/p38 MAPK pathway.

Cell Cycle 2019 Dec 9;18(23):3378-3392. Epub 2019 Oct 9.

State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology and Collaborative Innovation Center of Hematology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.

Retinoic acid inducible gene-I (Rig-I) has been well documented as a cytosolic pattern recognition receptor that can sense viral RNA ligands to initiate the interferon-mediated antiviral immunity. However, little is known about the biological behaviors of Rig-I devoid of viral infection. Herein, we investigated the roles of Rig-I in the regulation of cellular senescence. In comparison to wild-type counterparts, mice displayed the accelerated loss of hair, less responsiveness to gentle physical stimuli and shorten survival time. Likewise, Rig-I deficiency rendered mouse embryonic fibroblasts (MEFs) more susceptible to the serial passages-associated replicative senescence. By performing a transcriptome analysis, we identified integrins at the intersections of biological pathways affected by Rig-I. Among these, integrin β3 was negatively regulated by Rig-I, and significantly upregulated with the occurrence of senescence. Gene silencing of Itgb3 (encoding integrin β3) retarded the progression of cellular senescence in both WT and MEFs. Notably, this effect was more prominent in MEFs. Furthermore, p38 MAPK was a key downstream molecule for integrin β3-mediated senescence, and overactivated in senescent MEFs. Taken together, Rig-I deficiency contributes to cellular senescence through amplifying integrin β3/p38 MAPK signaling. Our findings provide the evidence that Rig-I is a key regulator of cellular senescence, which will be helpful in better understanding its function without viral infection. Rig-I: retinoic acid inducible gene-I; SASP: senescence-associated secretory phenotype; ECM: extracellular matrix; Itgb3: integrin beta 3; PRR: pattern recognition receptor; MEFs: mouse embryonic fibroblasts; Il-1β: interleukin-1 beta; Il-6: interleukin-6; Il-8: interleukin-8; Cxcl1: chemokine (C-X-C motif) ligand 1; Ccl2: chemokine (C-C motif) ligand 2; WT, wild type; BM: bone marrow; MAPK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinases; JNK: Jun N-terminal kinases; SA-β-gal: senescence-associated β-galactosidase; qPCR: quantitative reverse-transcription PCR; PBS: phosphate-buffered saline.
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http://dx.doi.org/10.1080/15384101.2019.1677074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927694PMC
December 2019

All-trans retinoic acid and arsenic trioxide fail to derepress the monocytic differentiation driver Irf8 in acute promyelocytic leukemia cells.

Cell Death Dis 2017 05 11;8(5):e2782. Epub 2017 May 11.

State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology and Collaborative Innovation Center of Hematology, Rui-Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

All-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO) administration leads to granulocytic maturation and/or apoptosis of acute promyelocytic leukemia (APL) cells mainly by targeting promyelocytic leukemia/retinoic acid receptor alpha (PML/RARα). Yet, ~10-15% of APL patients are not cured by ATRA- and ATO-based therapies, and a potential failure of ATRA and ATO in completely reversing PML/RARα-driven oncogenic alterations has not been comprehensively examined. Here we characterized the in vivo primary responses of dysregulated genes in APL cells treated with ATRA and ATO using a GFP-labeled APL model. Although induced granulocytic differentiation of APL cells was evident after ATRA or ATO administration, the expression of the majority of dysregulated genes in the c-Kit APL progenitors was not consistently corrected. Irf8, whose expression increased along with spontaneous differentiation of the APL progenitors in vivo, represented such a PML/RARα-dysregulated gene that was refractory to ATRA/ATO signaling. Interestingly, Irf8 induction, but not its knockdown, decreased APL leukemogenic potential through driving monocytic maturation. Thus, we reveal that certain PML/RARα-dysregulated genes that are refractory to ATRA/ATO signaling are potentially crucial regulators of the immature status and leukemogenic potential of APL cells, which can be exploited for the development of new therapeutic strategies for ATRA/ATO-resistant APL cases.
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http://dx.doi.org/10.1038/cddis.2017.197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520717PMC
May 2017

8-Oxoguanine DNA glycosylase 1 (ogg1) maintains the function of cardiac progenitor cells during heart formation in zebrafish.

Exp Cell Res 2013 Nov 24;319(19):2954-63. Epub 2013 Jul 24.

State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, China.

Genomic damage may devastate the potential of progenitor cells and consequently impair early organogenesis. We found that ogg1, a key enzyme initiating the base-excision repair, was enriched in the embryonic heart in zebrafish. So far, little is known about DNA repair in cardiogenesis. Here, we addressed the critical role of ogg1 in cardiogenesis for the first time. ogg1 mainly expressed in the anterior lateral plate mesoderm (ALPM), the primary heart tube, and subsequently the embryonic myocardium by in situ hybridisation. Loss of ogg1 resulted in severe cardiac morphogenesis and functional abnormalities, including the short heart length, arrhythmia, decreased cardiomyocytes and nkx2.5(+) cardiac progenitor cells. Moreover, the increased apoptosis and repressed proliferation of progenitor cells caused by ogg1 deficiency might contribute to the heart phenotype. The microarray analysis showed that the expression of genes involved in embryonic heart tube morphogenesis and heart structure were significantly changed due to the lack of ogg1. Among those, foxh1 is an important partner of ogg1 in the cardiac development in response to DNA damage. Our work demonstrates the requirement of ogg1 in cardiac progenitors and heart development in zebrafish. These findings may be helpful for understanding the aetiology of congenital cardiac deficits.
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http://dx.doi.org/10.1016/j.yexcr.2013.07.012DOI Listing
November 2013
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