DNA methylation patterns of β-globin cluster in β-thalassemia patients

Clin Epigenetics. 2020 Dec 3;12(1):187. doi: 10.1186/s13148-020-00987-2.

Abstract

Background: Reactivation of fetal hemoglobin (HbF, α2γ2) holds a therapeutic target for β-thalassemia and sickle cell disease. Although many HbF regulators have been identified, the methylation patterns in β-globin cluster driving the fetal-to-adult hemoglobin switch remains to be determined.

Results: Here, we evaluated DNA methylation patterns of the β-globin cluster from peripheral bloods of 105 β00 thalassemia patients and 44 normal controls. We also recruited 15 bone marrows and 4 cord blood samples for further evaluation. We identified that the CpG sites in the locus control region (LCR) DNase I hypersensitive site 4 and 3 (HS4-3) regions, and γ- and β-globin promoters displayed hypomethylation in β00-thalassemia patients, especially for the patients with high HbF level, as compared with normal controls. Furthermore, hypomethylations in most of CpG sites of the HS4-3 core regions were also observed in bone marrows (BM) of β00-patients compared with normal controls; and methylation level of γ-globin promoter -50 and + 17 CpG sites showed lower methylation level in patients with high HbF level compared with those with low HbF level and a negative correlation with HbF level among β0-thalassemia patients. Finally, γ-globin promoter + 17 and + 50 CpG sites also displayed significant hypomethylation in cord blood (CB) tissues compared with BM tissues from normal controls.

Conclusions: Our findings revealed methylation patterns in β-globin cluster associated with β0 thalassemia disease and γ-globin expression, contributed to understand the epigenetic modification in β0 thalassemia patients and provided candidate targets for the therapies of β-hemoglobinopathies.

Keywords: Bone marrow; Cord blood; Developmental stage; Fetal hemoglobin; Methylation patterns; β-globin cluster; β0 thalassemia patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Bone Marrow / metabolism
  • Case-Control Studies
  • Child
  • Child, Preschool
  • CpG Islands / genetics
  • DNA Methylation
  • Epigenesis, Genetic
  • Fetal Blood / metabolism
  • Fetal Hemoglobin / analysis
  • Fetal Hemoglobin / biosynthesis*
  • Fetal Hemoglobin / genetics
  • Humans
  • Promoter Regions, Genetic
  • beta-Globins / chemistry
  • beta-Globins / genetics*
  • beta-Globins / metabolism
  • beta-Thalassemia / blood*
  • beta-Thalassemia / genetics*
  • beta-Thalassemia / therapy
  • gamma-Globins / genetics
  • gamma-Globins / metabolism

Substances

  • beta-Globins
  • gamma-Globins
  • Fetal Hemoglobin