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Reactivation of a developmentally silenced embryonic globin gene.
King, Andrew J; Songdej, Duantida; Downes, Damien J; Beagrie, Robert A; Liu, Siyu; Buckley, Megan; Hua, Peng; Suciu, Maria C; Marieke Oudelaar, A; Hanssen, Lars L P; Jeziorska, Danuta; Roberts, Nigel; Carpenter, Stephanie J; Francis, Helena; Telenius, Jelena; Olijnik, Aude-Anais; Sharpe, Jacqueline A; Sloane-Stanley, Jacqueline; Eglinton, Jennifer; Kassouf, Mira T; Orkin, Stuart H; Pennacchio, Len A; Davies, James O J; Hughes, Jim R; Higgs, Douglas R; Babbs, Christian.
Affiliation
  • King AJ; MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • Songdej D; MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • Downes DJ; Division of Hematology/Oncology, Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
  • Beagrie RA; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • Liu S; MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • Buckley M; MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • Hua P; Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, UK.
  • Suciu MC; MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • Marieke Oudelaar A; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • Hanssen LLP; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • Jeziorska D; Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
  • Roberts N; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • Carpenter SJ; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • Francis H; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • Telenius J; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • Olijnik AA; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • Sharpe JA; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • Sloane-Stanley J; MRC WIMM Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
  • Eglinton J; MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • Kassouf MT; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • Orkin SH; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • Pennacchio LA; National Haemoglobinopathy Reference Laboratory, Department of Haematology, Level 4, John Radcliffe Hospital, Oxford, UK.
  • Davies JOJ; MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • Hughes JR; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA, USA.
  • Higgs DR; Functional Genomics Department, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
  • Babbs C; Comparative Biochemistry Program, University of California, Berkeley, CA, USA.
Nat Commun ; 12(1): 4439, 2021 07 21.
Article in En | MEDLINE | ID: mdl-34290235
ABSTRACT
The α- and ß-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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Transcriptional Activation / Gene Expression Regulation, Developmental / Gene Silencing / Zeta-Globins Limits: Animals / Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2021 Document type: Article Affiliation country: United kingdom
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Transcriptional Activation / Gene Expression Regulation, Developmental / Gene Silencing / Zeta-Globins Limits: Animals / Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2021 Document type: Article Affiliation country: United kingdom