C2H2 Zinc Finger Transcription Factors Associated with Hemoglobinopathies.

Xing Zhang, Fangfang Xia, Xiaotian Zhang, Robert M Blumenthal, Xiaodong Cheng

Journal: Journal of molecular biology 2024;436(7):168343

PMID: 37924864

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Abstract

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.

Address: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: [email protected].; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.; Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center Houston, McGovern Medical School, Houston, TX 77030, USA.; Department of Medical Microbiology and Immunology, and Program in Bioinformatics, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA.; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: [email protected].

DOI: 10.1016/j.jmb.2023.168343

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https://assays.cancer.gov/non-CPTAC-3551

MeSH Terms: Humans, Cell Line, Tumor, CYS2-HIS2 Zinc Fingers, DNA, DNA-Binding Proteins, Fetal Hemoglobin, gamma-Globins, Hemoglobinopathies, Repressor Proteins, Transcription Factors