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Journal Article

Reactivation of a developmentally silenced embryonic globin gene


Oudelaar,  A. M.
Lise Meitner Group Genome Organization and Regulation, MPI for Biophysical Chemistry, Max Planck Society;

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King, A. J., Songdej, D., Downes, D. J., Beagrie, R. A., Liu, S., Buckley, M., et al. (2021). Reactivation of a developmentally silenced embryonic globin gene. Nature Communications, 12: 4439. doi:10.1038/s41467-021-24402-3.

Cite as: https://hdl.handle.net/21.11116/0000-0008-EAA7-4
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.