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  Reactivation of a developmentally silenced embryonic globin gene

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.

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 Creators:
King, A. J., Author
Songdej, D., Author
Downes, D. J., Author
Beagrie, R. A., Author
Liu, S., Author
Buckley, M., Author
Hua, P., Author
Suciu, M. C., Author
Oudelaar, A. M.1, Author           
Hanssen, L. L. P., Author
Jeziorska, D., Author
Roberts, N., Author
Carpenter, S. J., Author
Francis, H., Author
Telenius, J., Author
Olijnik, A.-A., Author
Sharpe, J. A., Author
Sloane-Stanley, J., Author
Eglinton, J., Author
Kassouf, M. T., Author
Orkin, S. H., AuthorPennacchio, L. A., AuthorDavies, J. O. J., AuthorHughes, J. R., AuthorHiggs, D. R., AuthorBabbs, C., Author more..
Affiliations:
1Lise Meitner Group Genome Organization and Regulation, MPI for Biophysical Chemistry, Max Planck Society, ou_3261271              

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 Abstract: 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.

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Language(s): eng - English
 Dates: 2021-07-21
 Publication Status: Published online
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 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41467-021-24402-3
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Title: Nature Communications
Source Genre: Journal
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Pages: 15 Volume / Issue: 12 Sequence Number: 4439 Start / End Page: - Identifier: -