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...

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Autores principales:	Kuo-Ting Sun, Yu-Nan Huang, Kalaiselvi Palanisamy, Shih-Sheng Chang, I-Kuan Wang, Kang-Hsi Wu, Ping Chen, Ching-Tien Peng, Chi-Yuan Li
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/33270ab99fe9440bafd0a8146fbbd950
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spelling	oai:doaj.org-article:33270ab99fe9440bafd0a8146fbbd9502021-12-02T11:40:30ZReciprocal regulation of γ-globin expression by exo-miRNAs: Relevance to γ-globin silencing in β-thalassemia major10.1038/s41598-017-00150-72045-2322https://doaj.org/article/33270ab99fe9440bafd0a8146fbbd9502017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00150-7https://doaj.org/toc/2045-2322Abstract 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.Kuo-Ting SunYu-Nan HuangKalaiselvi PalanisamyShih-Sheng ChangI-Kuan WangKang-Hsi WuPing ChenChing-Tien PengChi-Yuan LiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kuo-Ting Sun Yu-Nan Huang Kalaiselvi Palanisamy Shih-Sheng Chang I-Kuan Wang Kang-Hsi Wu Ping Chen Ching-Tien Peng Chi-Yuan Li Reciprocal regulation of γ-globin expression by exo-miRNAs: Relevance to γ-globin silencing in β-thalassemia major
description	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.
format	article
author	Kuo-Ting Sun Yu-Nan Huang Kalaiselvi Palanisamy Shih-Sheng Chang I-Kuan Wang Kang-Hsi Wu Ping Chen Ching-Tien Peng Chi-Yuan Li
author_facet	Kuo-Ting Sun Yu-Nan Huang Kalaiselvi Palanisamy Shih-Sheng Chang I-Kuan Wang Kang-Hsi Wu Ping Chen Ching-Tien Peng Chi-Yuan Li
author_sort	Kuo-Ting Sun
title	Reciprocal regulation of γ-globin expression by exo-miRNAs: Relevance to γ-globin silencing in β-thalassemia major
title_short	Reciprocal regulation of γ-globin expression by exo-miRNAs: Relevance to γ-globin silencing in β-thalassemia major
title_full	Reciprocal regulation of γ-globin expression by exo-miRNAs: Relevance to γ-globin silencing in β-thalassemia major
title_fullStr	Reciprocal regulation of γ-globin expression by exo-miRNAs: Relevance to γ-globin silencing in β-thalassemia major
title_full_unstemmed	Reciprocal regulation of γ-globin expression by exo-miRNAs: Relevance to γ-globin silencing in β-thalassemia major
title_sort	reciprocal regulation of γ-globin expression by exo-mirnas: relevance to γ-globin silencing in β-thalassemia major
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/33270ab99fe9440bafd0a8146fbbd950
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Reciprocal regulation of γ-globin expression by exo-miRNAs: Relevance to γ-globin silencing in β-thalassemia major

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