TY - JOUR
T1 - C2H2 Zinc Finger Transcription Factors Associated with Hemoglobinopathies
AU - Zhang, Xing
AU - Xia, Fangfang
AU - Zhang, Xiaotian
AU - Blumenthal, Robert M.
AU - Cheng, Xiaodong
N1 - Publisher Copyright:
© 2023 The Author(s)
PY - 2024/4/1
Y1 - 2024/4/1
N2 - In humans, specific aberrations in β-globin results in sickle cell disease and β-thalassemia, symptoms of which can be ameliorated by increased expression of fetal globin (HbF). Two recent CRISPR-Cas9 screens, centered on ∼1500 annotated sequence-specific DNA binding proteins and performed in a human erythroid cell line that expresses adult hemoglobin, uncovered four groups of candidate regulators of HbF gene expression. They are (1) members of the nucleosome remodeling and deacetylase (NuRD) complex proteins that are already known for HbF control; (2) seven C2H2 zinc finger (ZF) proteins, including some (ZBTB7A and BCL11A) already known for directly silencing the fetal γ-globin genes in adult human erythroid cells; (3) a few other transcription factors of different structural classes that might indirectly influence HbF gene expression; and (4) DNA methyltransferase 1 (DNMT1) that maintains the DNA methylation marks that attract the MBD2-associated NuRD complex to DNA as well as associated histone H3 lysine 9 methylation. Here we briefly discuss the effects of these regulators, particularly C2H2 ZFs, in inducing HbF expression for treating β-hemoglobin disorders, together with recent advances in developing safe and effective small-molecule therapeutics for the regulation of this well-conserved hemoglobin switch.
AB - In humans, specific aberrations in β-globin results in sickle cell disease and β-thalassemia, symptoms of which can be ameliorated by increased expression of fetal globin (HbF). Two recent CRISPR-Cas9 screens, centered on ∼1500 annotated sequence-specific DNA binding proteins and performed in a human erythroid cell line that expresses adult hemoglobin, uncovered four groups of candidate regulators of HbF gene expression. They are (1) members of the nucleosome remodeling and deacetylase (NuRD) complex proteins that are already known for HbF control; (2) seven C2H2 zinc finger (ZF) proteins, including some (ZBTB7A and BCL11A) already known for directly silencing the fetal γ-globin genes in adult human erythroid cells; (3) a few other transcription factors of different structural classes that might indirectly influence HbF gene expression; and (4) DNA methyltransferase 1 (DNMT1) that maintains the DNA methylation marks that attract the MBD2-associated NuRD complex to DNA as well as associated histone H3 lysine 9 methylation. Here we briefly discuss the effects of these regulators, particularly C2H2 ZFs, in inducing HbF expression for treating β-hemoglobin disorders, together with recent advances in developing safe and effective small-molecule therapeutics for the regulation of this well-conserved hemoglobin switch.
KW - C2H2 zinc finger proteins
KW - protein-DNA interactions
KW - sickle cell disease
KW - β-globin locus
KW - β-thalassemia
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U2 - 10.1016/j.jmb.2023.168343
DO - 10.1016/j.jmb.2023.168343
M3 - Review article
C2 - 37924864
AN - SCOPUS:85176579050
SN - 0022-2836
VL - 436
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 7
M1 - 168343
ER -