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Reactivation of a developmentally silenced embryonic globin gene
- Source :
- Nature Communications, Nature communications, vol 12, iss 1, Nature Communications, Vol 12, Iss 1, Pp 1-15 (2021)
- Publication Year :
- 2020
-
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.<br />Globin loci harbor genes that are expressed embryonically and silenced postnatally. Here the authors show that zeta-globin silencing depends upon selective hypoacetylation of its TAD subdomain, which blocks its interaction with the alpha-globin super-enhancer, and zeta-globin can be reactivated by acetylation.
- Subjects :
- 0301 basic medicine
General Physics and Astronomy
Stem Cell Research - Embryonic - Non-Human
Mice
0302 clinical medicine
hemic and lymphatic diseases
Developmental
Regulation of gene expression
Multidisciplinary
biology
Molecular medicine
Cooley's Anemia
Haematopoietic stem cells
Gene Expression Regulation, Developmental
Gene silencing
Acetylation
Hematology
Chromatin
Cell biology
DNA-Binding Proteins
Histone
Enhancer Elements, Genetic
030220 oncology & carcinogenesis
Transcriptional Activation
Enhancer Elements
Heterochromatin
Science
Chromatin remodelling
General Biochemistry, Genetics and Molecular Biology
Article
03 medical and health sciences
Rare Diseases
Genetic
Erythroid Cells
alpha-Globins
Genetics
Animals
Humans
Globin
Gene Silencing
zeta-Globins
Enhancer
Gene
General Chemistry
Stem Cell Research
Embryonic stem cell
Gene regulation
Histone Deacetylase Inhibitors
Repressor Proteins
030104 developmental biology
Gene Expression Regulation
biology.protein
Transcription Factors
Subjects
Details
- ISSN :
- 20411723
- Volume :
- 12
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Nature communications
- Accession number :
- edsair.doi.dedup.....3c2e55d901b82c1f35bff2076e580a90