Open AccessNRF2 mediates γ-globin gene regulation through epigenetic modifications in a β-YAC transgenic mouse model
Author(s) -
Xiaofeng Zhu,
Caixia Xi,
Alexander H. Ward,
Mayuko Takezaki,
Huidong Shi,
Kenneth R. Peterson,
Betty S. Pace
Publication year - 2020
Publication title -
experimental biology and medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.012
H-Index - 146
eISSN - 1535-3702
pISSN - 1535-3699
DOI - 10.1177/1535370220945305
Subject(s) - epigenetics , fetal hemoglobin , biology , globin , transgene , chromatin , gene , hemoglobin , dna methylation , genetics , microbiology and biotechnology , gene expression , fetus , biochemistry , pregnancy
Sickle cell disease is an inherited hemoglobin disorder that affects over 100,000 people in the United States causing high morbidity and early mortality. Although new treatments were recently approved by the FDA, only one drug Hydroxyurea induces fetal hemoglobin expression to inhibit sickle hemoglobin polymerization in red blood cells. Our laboratory previously demonstrated the ability of the NRF2 activator, dimethyl fumarate to induce fetal hemoglobin in the sickle cell mouse model. In this study, we investigated molecular mechanisms of γ-globin gene activation by NRF2. We observed the ability of NRF2 to modulate chromatin structure in the human β-like globin gene locus of β-YAC transgenic mice during development. Furthermore, an NRF2/TET3 interaction regulates γ-globin gene DNA methylation. These findings provide potential new molecular targets for small molecule drug developed for treating sickle cell disease.