Reactivation of a developmentally silenced embryonic globin gene

Nat Commun. 2021 Jul 21;12(1):4439. doi: 10.1038/s41467-021-24402-3.


The α- and β-globin loci harbor developmentally expressed genes, which are silenced throughout post-natal life. Reactivation of these genes may offer therapeutic approaches for the hemoglobinopathies, the most common single gene disorders. Here, we address mechanisms regulating the embryonically expressed α-like globin, termed ζ-globin. We show that in embryonic erythroid cells, the ζ-gene lies within a ~65 kb sub-TAD (topologically associating domain) of open, acetylated chromatin and interacts with the α-globin super-enhancer. By contrast, in adult erythroid cells, the ζ-gene is packaged within a small (~10 kb) sub-domain of hypoacetylated, facultative heterochromatin within the acetylated sub-TAD and that it no longer interacts with its enhancers. The ζ-gene can be partially re-activated by acetylation and inhibition of histone de-acetylases. In addition to suggesting therapies for severe α-thalassemia, these findings illustrate the general principles by which reactivation of developmental genes may rescue abnormalities arising from mutations in their adult paralogues.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetylation
  • Animals
  • Chromatin / metabolism
  • DNA-Binding Proteins / metabolism
  • Enhancer Elements, Genetic
  • Erythroid Cells / metabolism
  • Gene Expression Regulation, Developmental* / drug effects
  • Gene Silencing* / drug effects
  • Histone Deacetylase Inhibitors / pharmacology
  • Humans
  • Mice
  • Repressor Proteins / metabolism
  • Transcription Factors / metabolism
  • Transcriptional Activation* / drug effects
  • alpha-Globins / genetics
  • zeta-Globins / genetics*


  • BCL11A protein, human
  • Chromatin
  • DNA-Binding Proteins
  • Histone Deacetylase Inhibitors
  • Repressor Proteins
  • Transcription Factors
  • ZBTB7A protein, human
  • alpha-Globins
  • zeta-Globins