Reactivation of developmentally silenced globin genes by forced chromatin looping.
Cell
; 158(4): 849-860, 2014 Aug 14.
Article
em En
| MEDLINE
| ID: mdl-25126789
ABSTRACT
Distal enhancers commonly contact target promoters via chromatin looping. In erythroid cells, the locus control region (LCR) contacts ß-type globin genes in a developmental stage-specific manner to stimulate transcription. Previously, we induced LCR-promoter looping by tethering the self-association domain (SA) of Ldb1 to the ß-globin promoter via artificial zinc fingers. Here, we show that targeting the SA to a developmentally silenced embryonic globin gene in adult murine erythroblasts triggers its transcriptional reactivation. This activity depends on the LCR, consistent with an LCR-promoter looping mechanism. Strikingly, targeting the SA to the fetal γ-globin promoter in primary adult human erythroblasts increases γ-globin promoter-LCR contacts, stimulating transcription to approximately 85% of total ß-globin synthesis, with a reciprocal reduction in adult ß-globin expression. Our findings demonstrate that forced chromatin looping can override a stringent developmental gene expression program and suggest a novel approach to control the balance of globin gene transcription for therapeutic applications.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Hemoglobina Fetal
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Cromatina
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Ativação Transcricional
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Técnicas Genéticas
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Região de Controle de Locus Gênico
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Globinas beta
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article