Reactivation of a developmentally silenced embryonic globin gene

Andrew J. King, Duantida Songdej, Damien J. Downes, Robert A. Beagrie, Siyu Liu, Megan Buckley, Peng Hua, Maria C. Suciu, A. Marieke Oudelaar, Lars L. P. Hanssen, Danuta Jeziorska, Nigel Roberts, Stephanie J. Carpenter, Helena Francis, Jelena Telenius, Aude-Anais Olijnik, Jacqueline A. Sharpe, Jacqueline Sloane-Stanley, Jennifer Eglinton, Mira T. Kassouf, Stuart H. Orkin, Len A. Pennacchio, James O. J. Davies, Jim R. Hughes, Douglas R. Higgs () and Christian Babbs ()
Additional contact information
Andrew J. King: University of Oxford
Duantida Songdej: University of Oxford
Damien J. Downes: University of Oxford
Robert A. Beagrie: University of Oxford
Siyu Liu: University of Oxford
Megan Buckley: University of Oxford
Peng Hua: University of Oxford
Maria C. Suciu: University of Oxford
A. Marieke Oudelaar: Max Planck Institute for Biophysical Chemistry
Lars L. P. Hanssen: University of Oxford
Danuta Jeziorska: University of Oxford
Nigel Roberts: University of Oxford
Stephanie J. Carpenter: University of Oxford
Helena Francis: University of Oxford
Jelena Telenius: University of Oxford
Aude-Anais Olijnik: University of Oxford
Jacqueline A. Sharpe: University of Oxford
Jacqueline Sloane-Stanley: University of Oxford
Jennifer Eglinton: John Radcliffe Hospital
Mira T. Kassouf: University of Oxford
Stuart H. Orkin: Harvard Medical School and Howard Hughes Medical Institute
Len A. Pennacchio: Lawrence Berkeley National Laboratory
James O. J. Davies: University of Oxford
Jim R. Hughes: University of Oxford
Douglas R. Higgs: University of Oxford
Christian Babbs: University of Oxford

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24402-3

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