Fetal Globin Gene Repressors as Drug Targets for Molecular Therapies To Treat the β-Globinopathies

Abstract

The human β-globin locus is comprised of embryonic, fetal, and adult globin genes that are expressed in a developmental stage-specific manner. Mutations in the globin locus give rise to the β-globinopathies, β-thalassemia and sickle cell disease, which begin to manifest symptoms around the time of birth. Although the fetal globin genes are autonomously silenced in adult-stage erythroid cells, mutations lying both within and outside the locus lead to natural variations in the level of fetal globin gene expression, and some of these significantly ameliorate the clinical symptoms of the β-globinopathies. Multiple reports have now identified several transcription factors that are involved in fetal globin gene repression in definitive (adult)-stage erythroid cells (the TR2/TR4 heterodimer, MYB, KLFs, BCL11A, and SOX6). To carry out their repression functions, chromatin-modifying enzymes (such as DNA methyltransferase, histone deacetylases, and lysine-specific histone demethylase 1) are additionally involved as a consequence of forming large macromolecular complexes with the DNA-binding subunits of these cellular machines. This review focuses on the molecular mechanisms underlying fetal globin gene silencing and possible near-future molecularly targeted therapies for treating the β-globinopathies.

ACKNOWLEDGMENTS

We are grateful to our colleagues Shuaiying Cui and Mary Lee, and to an unknown referee, for careful editing of the manuscript and for providing significant insight and perspective.

This work was supported by the NIH (R21HL114368 and U01HL117658 to J.D.E.) and the JSPS (KAKENHI 22118001 and 24249015 to M.Y. and 26461395 to M.S.).