Activation of γ-globin expression by LncRNA-mediated ERF promoter hypermethylation in β-thalassemia

Xiuqin Bao; Yuanyi Gao; Zhongju Wang; Yuhua Ye; Diyu Chen; Yangjin Zuo; Cunyou Zhao; Xiangmin Xu

doi:10.1186/s13148-023-01614-6

Activation of γ-globin expression by LncRNA-mediated ERF promoter hypermethylation in β-thalassemia

Clin Epigenetics. 2024 Jan 13;16(1):12. doi: 10.1186/s13148-023-01614-6.

Authors

Xiuqin Bao^{1

2

3

4}, Yuanyi Gao^{5

2

3}, Zhongju Wang^{2

3}, Yuhua Ye^{2

3}, Diyu Chen^{2

3}, Yangjin Zuo^{2

3}, Cunyou Zhao^{6

7

8}, Xiangmin Xu^{9

10

11}

Affiliations

¹ Medical Genetic Center, Guangdong Women and Children Hospital, Guangzhou, 514000, Guangdong, China.
² Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China.
³ Guangdong Engineering and Technology Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, 510515, Guangdong, China.
⁴ Maternal and Children Metabolic-Genetic Key Laboratory, Guangdong Women and Children Hospital, Guangzhou, 514000, Guangdong, China.
⁵ Innovation Center for Diagnostics and Treatment of Thalassemia, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.
⁶ Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China. zhaocunyou@gmail.com.
⁷ Guangdong Engineering and Technology Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, 510515, Guangdong, China. zhaocunyou@gmail.com.
⁸ Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, and Guangdong Province Key Laboratory of Psychiatric Disorders, Southern Medical University, Guangzhou, China. zhaocunyou@gmail.com.
⁹ Innovation Center for Diagnostics and Treatment of Thalassemia, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China. gzxuxm@pub.guangzhou.gd.cn.
¹⁰ Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China. gzxuxm@pub.guangzhou.gd.cn.
¹¹ Guangdong Engineering and Technology Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, 510515, Guangdong, China. gzxuxm@pub.guangzhou.gd.cn.

Abstract

The mechanism that drives the switch from fetal to adult hemoglobin (Hb) provides a therapeutic target for β-thalassemia. We have previously identified that hypermethylation of transcription factor ERF promoter reactivated γ-globin expression. To uncover the mechanism underlying the hypermethylation of ERF promoter, we performed RNA sequencing in β⁰/β⁰-thalassemia patients and identified an upregulated long noncoding RNA (RP11-196G18.23) associated with HbF production. RP11-196G18.23 bound to the ERF promoter and recruited DNA methyltransferase 3A to promote DNA hypermethylation-mediated ERF downregulation, thereby ameliorating ERF-induced γ-globin inactivation. The identification of RP11-196G18.23 provides an epigenetic mechanism for the reactivation of fetal γ-globin expression for β-hemoglobinopathies.

Keywords: ERF promoter hypermethylation; Fetal hemoglobin; RP11-196G18.23; β-Thalassemia; γ-Globin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
DNA Methylation
Fetal Hemoglobin / genetics
Humans
RNA, Long Noncoding* / genetics
RNA, Long Noncoding* / metabolism
Repressor Proteins / genetics
beta-Thalassemia* / genetics
beta-Thalassemia* / therapy
gamma-Globins / genetics
gamma-Globins / metabolism

Substances

gamma-Globins
RNA, Long Noncoding
Fetal Hemoglobin
ERF protein, human
Repressor Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding