Fetal globin gene repressors as drug targets for molecular therapies to treat the β-globinopathies

Mikiko Suzuki, Masayuki Yamamoto, James Douglas Engel

Research output: Contribution to journalShort surveypeer-review

46 Citations (Scopus)

Abstract

The human β-globin locus is comprised of embryonic, fetal, and adult globin genes that are expressed in a developmental stagespecific 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.

Original languageEnglish
Pages (from-to)3560-3569
Number of pages10
JournalMolecular and cellular biology
Volume34
Issue number19
DOIs
Publication statusPublished - 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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