The GATA1-HS2 enhancer allows persistent and position-independent expression of a β-globin transgene.
Gene therapy of genetic diseases requires persistent and position-independent expression of a therapeutic transgene. Transcriptional enhancers binding chromatin-remodeling and modifying complexes may play a role in shielding transgenes from repressive chromatin effects. We tested the activity of the...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2011-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3229501?pdf=render |
| _version_ | 1818691667526418432 |
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| author | Annarita Miccio Valentina Poletti Francesca Tiboni Claudia Rossi Antonella Antonelli Fulvio Mavilio Giuliana Ferrari |
| author_facet | Annarita Miccio Valentina Poletti Francesca Tiboni Claudia Rossi Antonella Antonelli Fulvio Mavilio Giuliana Ferrari |
| author_sort | Annarita Miccio |
| collection | DOAJ |
| description | Gene therapy of genetic diseases requires persistent and position-independent expression of a therapeutic transgene. Transcriptional enhancers binding chromatin-remodeling and modifying complexes may play a role in shielding transgenes from repressive chromatin effects. We tested the activity of the HS2 enhancer of the GATA1 gene in protecting the expression of a β-globin minigene delivered by a lentiviral vector in hematopoietic stem/progenitor cells. Gene expression from proviruses carrying GATA1-HS2 in both LTRs was persistent and resistant to silencing at most integration sites in the in vivo progeny of human hematopoietic progenitors and murine long-term repopulating stem cells. The GATA1-HS2-modified vector allowed correction of murine β-thalassemia at low copy number without inducing clonal selection of erythroblastic progenitors. Chromatin immunoprecipitation studies showed that GATA1 and the CBP acetyltransferase bind to GATA1-HS2, significantly increasing CBP-specific histone acetylations at the LTRs and β-globin promoter. Recruitment of CBP by the LTRs thus establishes an open chromatin domain encompassing the entire provirus, and increases the therapeutic efficacy of β-globin gene transfer by reducing expression variegation and epigenetic silencing. |
| first_indexed | 2024-12-17T12:45:32Z |
| format | Article |
| id | doaj.art-1fc652a484ed43868d2ec7d30b5d9a20 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-17T12:45:32Z |
| publishDate | 2011-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-1fc652a484ed43868d2ec7d30b5d9a202022-12-21T21:47:44ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-01612e2795510.1371/journal.pone.0027955The GATA1-HS2 enhancer allows persistent and position-independent expression of a β-globin transgene.Annarita MiccioValentina PolettiFrancesca TiboniClaudia RossiAntonella AntonelliFulvio MavilioGiuliana FerrariGene therapy of genetic diseases requires persistent and position-independent expression of a therapeutic transgene. Transcriptional enhancers binding chromatin-remodeling and modifying complexes may play a role in shielding transgenes from repressive chromatin effects. We tested the activity of the HS2 enhancer of the GATA1 gene in protecting the expression of a β-globin minigene delivered by a lentiviral vector in hematopoietic stem/progenitor cells. Gene expression from proviruses carrying GATA1-HS2 in both LTRs was persistent and resistant to silencing at most integration sites in the in vivo progeny of human hematopoietic progenitors and murine long-term repopulating stem cells. The GATA1-HS2-modified vector allowed correction of murine β-thalassemia at low copy number without inducing clonal selection of erythroblastic progenitors. Chromatin immunoprecipitation studies showed that GATA1 and the CBP acetyltransferase bind to GATA1-HS2, significantly increasing CBP-specific histone acetylations at the LTRs and β-globin promoter. Recruitment of CBP by the LTRs thus establishes an open chromatin domain encompassing the entire provirus, and increases the therapeutic efficacy of β-globin gene transfer by reducing expression variegation and epigenetic silencing.http://europepmc.org/articles/PMC3229501?pdf=render |
| spellingShingle | Annarita Miccio Valentina Poletti Francesca Tiboni Claudia Rossi Antonella Antonelli Fulvio Mavilio Giuliana Ferrari The GATA1-HS2 enhancer allows persistent and position-independent expression of a β-globin transgene. PLoS ONE |
| title | The GATA1-HS2 enhancer allows persistent and position-independent expression of a β-globin transgene. |
| title_full | The GATA1-HS2 enhancer allows persistent and position-independent expression of a β-globin transgene. |
| title_fullStr | The GATA1-HS2 enhancer allows persistent and position-independent expression of a β-globin transgene. |
| title_full_unstemmed | The GATA1-HS2 enhancer allows persistent and position-independent expression of a β-globin transgene. |
| title_short | The GATA1-HS2 enhancer allows persistent and position-independent expression of a β-globin transgene. |
| title_sort | gata1 hs2 enhancer allows persistent and position independent expression of a β globin transgene |
| url | http://europepmc.org/articles/PMC3229501?pdf=render |
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