title: Reciprocal regulation of γ-globin expression by exo-miRNAs: Relevance to γ-globin silencing in β-thalassemia major.
abstract: Induction of fetal hemoglobin (HbF) is a promising strategy in the treatment of β-thalassemia major (β-TM). The present study shows that plasma exosomal miRNAs (exo-miRs) are involved in γ-globin regulation. Exosomes shuttle miRNAs and mediate cell-cell communication. MiRNAs are regulators of biological processes through post-transcriptional targeting. Compared to HD (Healthy Donor), β-TM patients showed increased levels of plasma exosomes and the majority of exosomes had cellular origin from CD34+ cells. Further, HD and β-TM exosomes showed differential miRNA expressions. Among them, deregulated miR-223-3p and miR-138-5p in β-TM exosomes and HD had specific targets for γ-globin regulator and repressor respectively. Functional studies in K562 cells showed that HD exosomes and miR-138-5p regulated γ-globin expression by targeting BCL11A. β-TM exosomes and miR-223-3p down regulated γ-globin expression through LMO2 targeting. Importantly, miR-223-3p targeting through sponge repression resulted in γ-globin activation. Further, hnRNPA1 bound to stem-loop structure of pre-miR-223 and we found that hnRNPA1 knockdown or mutagenesis at miR-223-3p stem-loop sequence resulted in less mature exo-miR-223-3p levels. Altogether, the study shows for the first time on the important clinical evidence that differentially expressed exo-miRNAs reciprocally control γ-globin expressions. Further, the hnRNPA1-exo-miR-223-LMO2 axis may be critical to γ-globin silencing in β-TM.
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, 40402, Taiwan.|Department of Pediatric Dentistry, China Medical University Hospital, Taichung, 40402, Taiwan.|School of Dentistry, China Medical University, Taichung, 40402, Taiwan.
authors.forename: Kuo-Ting
authors.initials: KT
authors.lastname: Sun
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, 40402, Taiwan.|Department of Life Sciences, National Chung-Hsing University, Taichung, 40402, Taiwan.|Department of Hematology-oncology, Children's Hospital of China Medical University, Taichung, 40402, Taiwan.
authors.forename: Yu-Nan
authors.initials: YN
authors.lastname: Huang
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, 40402, Taiwan.
authors.forename: Kalaiselvi
authors.initials: K
authors.lastname: Palanisamy
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, 40402, Taiwan.|Division of Cardiology, Department of Medicine, China Medical University Hospital, Taichung, 40402, Taiwan.
authors.forename: Shih-Sheng
authors.initials: SS
authors.lastname: Chang
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, 40402, Taiwan.|Division of Nephrology, Department of Medicine, China Medical University Hospital, Taichung, 40402, Taiwan.
authors.forename: I-Kuan
authors.initials: IK
authors.lastname: Wang
authors.affiliation: Department of Hematology-oncology, Children's Hospital of China Medical University, Taichung, 40402, Taiwan.
authors.forename: Kang-Hsi
authors.initials: KH
authors.lastname: Wu
authors.affiliation: Thalassemia Research Institute, The First Affiliated Hospital, Guangxi Medical University, Guangxi Zhuang Autonomous Region, 530021, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Hematology-oncology, Children's Hospital of China Medical University, Taichung, 40402, Taiwan. pct@mail.cmuh.org.tw.
authors.forename: Ching-Tien
authors.initials: CT
authors.lastname: Peng
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, 40402, Taiwan. cyli168@gmail.com.|Department of Anesthesiology, China Medical University Hospital, Taichung, 40402, Taiwan. cyli168@gmail.com.
authors.forename: Chi-Yuan
authors.initials: CY
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins / Q000235:genetics; D002450:Cell Communication; D015536:Down-Regulation; D055354:Exosomes / Q000235:genetics*; D005260:Female; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1 / Q000235:genetics; D006801:Humans; D020014:K562 Cells; D060588:LIM Domain Proteins / Q000235:genetics; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012097:Repressor Proteins; D055815:Young Adult; D017086:beta-Thalassemia / Q000235:genetics*; D055545:gamma-Globins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D060588:LIM Domain Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D055545:gamma-Globins; C486563:BCL11A protein, human; C085117:LMO2 protein, human; C546110:MIRN138 microRNA, human; C525067:MIR223, human; C000619656:hnRNPA1 protein, human