Reactivation of a developmentally silenced embryonic globin gene
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 exp...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2021
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| _version_ | 1826307577250578432 |
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| author | King, AJ Songdej, D Downes, DJ Beagrie, RA Liu, S Buckley, M Hua, P Suciu, MC Marieke Oudelaar, A Hanssen, LLP Jeziorska, D Roberts, N Carpenter, SJ Francis, H Telenius, J Olijnik, A-A Sharpe, JA Sloane-Stanley, J Eglinton, J Kassouf, MT Orkin, SH Pennacchio, LA Davies, JOJ Hughes, JR Higgs, DR Babbs, C |
| author_facet | King, AJ Songdej, D Downes, DJ Beagrie, RA Liu, S Buckley, M Hua, P Suciu, MC Marieke Oudelaar, A Hanssen, LLP Jeziorska, D Roberts, N Carpenter, SJ Francis, H Telenius, J Olijnik, A-A Sharpe, JA Sloane-Stanley, J Eglinton, J Kassouf, MT Orkin, SH Pennacchio, LA Davies, JOJ Hughes, JR Higgs, DR Babbs, C |
| author_sort | King, AJ |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T07:05:11Z |
| format | Journal article |
| id | oxford-uuid:b6d5fd3f-ebbb-4264-bd57-7dcc1a815018 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:05:11Z |
| publishDate | 2021 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:b6d5fd3f-ebbb-4264-bd57-7dcc1a8150182022-04-22T14:34:39ZReactivation of a developmentally silenced embryonic globin geneJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:b6d5fd3f-ebbb-4264-bd57-7dcc1a815018EnglishSymplectic ElementsSpringer Nature2021King, AJSongdej, DDownes, DJBeagrie, RALiu, SBuckley, MHua, PSuciu, MCMarieke Oudelaar, AHanssen, LLPJeziorska, DRoberts, NCarpenter, SJFrancis, HTelenius, JOlijnik, A-ASharpe, JASloane-Stanley, JEglinton, JKassouf, MTOrkin, SHPennacchio, LADavies, JOJHughes, JRHiggs, DRBabbs, CThe 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. |
| spellingShingle | King, AJ Songdej, D Downes, DJ Beagrie, RA Liu, S Buckley, M Hua, P Suciu, MC Marieke Oudelaar, A Hanssen, LLP Jeziorska, D Roberts, N Carpenter, SJ Francis, H Telenius, J Olijnik, A-A Sharpe, JA Sloane-Stanley, J Eglinton, J Kassouf, MT Orkin, SH Pennacchio, LA Davies, JOJ Hughes, JR Higgs, DR Babbs, C Reactivation of a developmentally silenced embryonic globin gene |
| title | Reactivation of a developmentally silenced embryonic globin gene |
| title_full | Reactivation of a developmentally silenced embryonic globin gene |
| title_fullStr | Reactivation of a developmentally silenced embryonic globin gene |
| title_full_unstemmed | Reactivation of a developmentally silenced embryonic globin gene |
| title_short | Reactivation of a developmentally silenced embryonic globin gene |
| title_sort | reactivation of a developmentally silenced embryonic globin gene |
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