Human m6A-mRNA and lncRNA epitranscriptomic microarray reveal function of RNA methylation in hemoglobin H-constant spring disease

Heyun Ruan,Xiaoli Zhang,Dongmei Yang,Lingjie Deng,Xueyu Li,Lihong Pang,Fang Yang

doi:10.1038/s41598-021-99867-9

Abstract

The thalassemia of Hemoglobin H-Constant Spring disease (HbH-CS) is the most common type of Thalassemia in non-transfusion thalassemia. Interestingly, the clinical manifestations of the same genotype of thalassemia can be vastly different, likely due to epigenetic regulation. Here, we used microarray technology to reveal the epigenetic regulation of m6A in modifiable diseases and demonstrated a role of BCL2A1 in disease regulation. In this study, we revealed that methylating enzyme writers including METTL16, WTAP, CBLL1, RBM15B, and ZC3H13 displayed low expression and the demethylating enzyme ALKBH5, along with reader proteins including IGF2BP2 and YTHDF3 exhibited high expression. In addition, BCL2A1 was hypo-methylated and showed low expression. We also revealed that the BCL2A1 methylation level and IGF2BP2 expression were negatively correlated. Additionally, the mRNAs expression between ALKBH5 and IGF2BP2 were positively correlated. In HbH-CS, most genes were hypo-methylated. This included BCL2A1, which may play an important role in the process of red blood cell differentiation and development of HbH-CS. Moreover, the mRNA-M6A methylation status may be regulated by the demethylating enzyme ALKBH5 via IGF2BP2.

Highlights

The clinical manifestations of Hemoglobin H Constant Spring (HbH-CS) thalassemia greatly vary in severity and cannot be explained solely by the causative genes related to thalassemia intermedia[3]
We observed no discernible differences in the age or gender of the HbH-CS thalassemia (T) and healthy volunteers (N) cohorts (Table 1)
We demonstrated that the mRNA expression and m 6A levels of BCL2A1 were markedly down-regulated in T versus N (Fig. 5B,C)

Summary

Introduction

Thalassemia is a serious genetic hemolytic anemic disease that destroys human health and brings about disability and/or death. Various forms of this disease are caused by a defect in the Globin gene, which reduces or completely ceases globin chain synthesis, thereby creating an imbalance in the chain/non-chain ratio of hemoglobin formation[1]. The Hemoglobin H Constant Spring (HbH-CS) is the most common non-deletion form of the Haemoglobin H disease. It is more severe in nature, as compared to thalassemia alone[2].

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Conclusion