Genome-wide analysis of aberrantly expressed lncRNAs and miRNAs with associated co-expression and ceRNA networks in β-thalassemia and hereditary persistence of fetal hemoglobin.

Ketong Lai,Shanjuan Yu,Siyuan Jia,Yunyan He,Jianming Luo

doi:10.18632/oncotarget.18263

Ketong Lai, Shanjuan Yu + Show 3 more

Open Access

https://doi.org/10.18632/oncotarget.18263

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Abstract

The implications of lncRNAs regarding fetal hemoglobin (HbF) induction in hemoglobin disorders remain poorly understood. In this study, microarray analysis was performed to profile lncRNAs, miRNAs and mRNAs in individuals with hereditary persistence of fetal hemoglobin (HPFH), β-thalassemia carriers with high HbF levels and healthy controls. The results show aberrant expression of 862 lncRNAs, 568 mRNAs and 63 miRNAs in the high-HbF group compared with the control group. Altered NR_001589, NR_120526, T315543, miR-486-3p, miR-19b-1-5p and miR-20a-3p expression was confirmed by quantitative reverse transcription-polymerase chain reaction, and Spearman correlation coefficients revealed significant positive correlations with HbF. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses showed the hematopoietic cell lineage and apoptosis to be most significantly dysregulated in HbF induction. We analyzed coding genes near the lncRNAs and constructed a coding-noncoding co-expression network. Based on the results, lncRNAs likely contribute to increased HbF levels by activating expression of HBE1 and hematopoietic cell lineage-inducible molecules and by inhibiting that of apoptosis-inducible molecules. Finally, through construction of a competing endogenous RNA network, we found that 6 lncRNAs could bind competitively with miR-486-3p, resulting in increased HbF levels. Taken together, our findings provide new insights into the mechanisms of HbF induction and potentially provide new targets for the treatment of β-thalassemia major.

Highlights

Β-Thalassemia, one of the most common genetic disorders worldwide, is endemic in many tropical and sub-tropical areas, such as Mediterranean countries, the Middle East, North African, the Indian subcontinent and Southeast Asia [1]
The results show aberrant expression of 862 long noncoding RNAs (lncRNAs), 568 mRNAs and 63 miRNAs in the high-fetal hemoglobin (HbF) group compared with the control group
Southern China has a high prevalence of thalassemia, in the Guangxi Zhuang Autonomous Region, where the total heterozygote frequency of thalassemia is 24.51% [2]. β-Thalassemia is caused by mutations, small deletions or insertions of one or two nucleotides in the β-globin genes. β-Thalassemia minor, which is caused by deficiency in one β-globin gene, can be asymptomatic or cause mild anemia

Summary

Introduction

Β-Thalassemia, one of the most common genetic disorders worldwide, is endemic in many tropical and sub-tropical areas, such as Mediterranean countries, the Middle East, North African, the Indian subcontinent and Southeast Asia [1]. When the γ-globin gene is switched off at approximately the age of 4-6 months and there is little or no β-globin expression, severely progressive anemia occurs. These patients require lifelong transfusions and iron chelation therapy at regular intervals for survival [4]; if not regularly treated with transfusion, the majority of β-thalassemia major patients will die by 5 years of age [5]. 10-20% of transcripts encode proteins (mRNAs) and 80%-90% of transcripts are non-protein-coding RNAs that are not translated These include microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). No studies have focused on the involvement of lncRNAs in hemoglobin disorders and their effects on HbF induction

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