An Erythroid Enhancer of BCL11A Subject to Genetic Variation Determines Fetal Hemoglobin Level.
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| Title: | An Erythroid Enhancer of BCL11A Subject to Genetic Variation Determines Fetal Hemoglobin Level. |
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| Authors: | Bauer, Daniel E., Kamran, Sophia C., Lessard, Samuel, Jian Xu, Yuko Fujiwara, Carrie Lin, Zhen Shao, Canver, Matthew C., Smith, Elenoe C., Pinello, Luca, Sabo, Peter J., Vierstra, Jeff, Voit, Richard A., Guo-Cheng Yuan, Porteus, Matthew H., Stamatoyannopoulos, John A., Lettre, Guillaume, Orkin, Stuart H. |
| Source: | Science (pre-March 2025). 10/11/2013, Vol. 342 Issue 6155, preceding p253-257. 6p. |
| Subjects: | Hemoglobinopathy, Erythrocyte membranes, Transcription factors, Fetus, Genetics, Chromatin, Gene expression, B cells, Health |
| Abstract: | Genome-wide association studies (GWASs) have ascertained numerous trait-associated common genetic variants, frequently localized to regulatory DNA. We found that common genetic variation at BCL11A associated with fetal hemoglobin (HbF) level lies in noncoding sequences decorated by an erythroid enhancer chromatin signature. Fine-mapping uncovers a motif-disrupting common variant associated with reduced transcription factor (TF) binding, modestly diminished BCL11A expression, and elevated HbF. The surrounding sequences function in vivo as a developmental stage-specific, lineage-restricted enhancer. Genome engineering reveals the enhancer is required in erythroid but not B-lymphoid cells for BCL11A expression. These findings illustrate how GWASs may expose functional variants of modest impact within causal elements essential for appropriate gene expression. We propose the GWAS-marked BCL11A enhancer represents an attractive target for therapeutic genome engineering for the b-hemoglobinopathies. [ABSTRACT FROM AUTHOR] |
| Copyright of Science (pre-March 2025) is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Psychology and Behavioral Sciences Collection |
| FullText | Links: – Type: pdflink Text: Availability: 0 |
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| Header | DbId: pbh DbLabel: Psychology and Behavioral Sciences Collection An: 90658805 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: An Erythroid Enhancer of BCL11A Subject to Genetic Variation Determines Fetal Hemoglobin Level. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Bauer%2C+Daniel+E%2E%22">Bauer, Daniel E.</searchLink><br /><searchLink fieldCode="AR" term="%22Kamran%2C+Sophia+C%2E%22">Kamran, Sophia C.</searchLink><br /><searchLink fieldCode="AR" term="%22Lessard%2C+Samuel%22">Lessard, Samuel</searchLink><br /><searchLink fieldCode="AR" term="%22Jian+Xu%22">Jian Xu</searchLink><br /><searchLink fieldCode="AR" term="%22Yuko+Fujiwara%22">Yuko Fujiwara</searchLink><br /><searchLink fieldCode="AR" term="%22Carrie+Lin%22">Carrie Lin</searchLink><br /><searchLink fieldCode="AR" term="%22Zhen+Shao%22">Zhen Shao</searchLink><br /><searchLink fieldCode="AR" term="%22Canver%2C+Matthew+C%2E%22">Canver, Matthew C.</searchLink><br /><searchLink fieldCode="AR" term="%22Smith%2C+Elenoe+C%2E%22">Smith, Elenoe C.</searchLink><br /><searchLink fieldCode="AR" term="%22Pinello%2C+Luca%22">Pinello, Luca</searchLink><br /><searchLink fieldCode="AR" term="%22Sabo%2C+Peter+J%2E%22">Sabo, Peter J.</searchLink><br /><searchLink fieldCode="AR" term="%22Vierstra%2C+Jeff%22">Vierstra, Jeff</searchLink><br /><searchLink fieldCode="AR" term="%22Voit%2C+Richard+A%2E%22">Voit, Richard A.</searchLink><br /><searchLink fieldCode="AR" term="%22Guo-Cheng+Yuan%22">Guo-Cheng Yuan</searchLink><br /><searchLink fieldCode="AR" term="%22Porteus%2C+Matthew+H%2E%22">Porteus, Matthew H.</searchLink><br /><searchLink fieldCode="AR" term="%22Stamatoyannopoulos%2C+John+A%2E%22">Stamatoyannopoulos, John A.</searchLink><br /><searchLink fieldCode="AR" term="%22Lettre%2C+Guillaume%22">Lettre, Guillaume</searchLink><br /><searchLink fieldCode="AR" term="%22Orkin%2C+Stuart+H%2E%22">Orkin, Stuart H.</searchLink> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Science+%28pre-March+2025%29%22">Science (pre-March 2025)</searchLink>. 10/11/2013, Vol. 342 Issue 6155, preceding p253-257. 6p. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Hemoglobinopathy%22">Hemoglobinopathy</searchLink><br /><searchLink fieldCode="DE" term="%22Erythrocyte+membranes%22">Erythrocyte membranes</searchLink><br /><searchLink fieldCode="DE" term="%22Transcription+factors%22">Transcription factors</searchLink><br /><searchLink fieldCode="DE" term="%22Fetus%22">Fetus</searchLink><br /><searchLink fieldCode="DE" term="%22Genetics%22">Genetics</searchLink><br /><searchLink fieldCode="DE" term="%22Chromatin%22">Chromatin</searchLink><br /><searchLink fieldCode="DE" term="%22Gene+expression%22">Gene expression</searchLink><br /><searchLink fieldCode="DE" term="%22B+cells%22">B cells</searchLink><br /><searchLink fieldCode="DE" term="%22Health%22">Health</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: Genome-wide association studies (GWASs) have ascertained numerous trait-associated common genetic variants, frequently localized to regulatory DNA. We found that common genetic variation at BCL11A associated with fetal hemoglobin (HbF) level lies in noncoding sequences decorated by an erythroid enhancer chromatin signature. Fine-mapping uncovers a motif-disrupting common variant associated with reduced transcription factor (TF) binding, modestly diminished BCL11A expression, and elevated HbF. The surrounding sequences function in vivo as a developmental stage-specific, lineage-restricted enhancer. Genome engineering reveals the enhancer is required in erythroid but not B-lymphoid cells for BCL11A expression. These findings illustrate how GWASs may expose functional variants of modest impact within causal elements essential for appropriate gene expression. We propose the GWAS-marked BCL11A enhancer represents an attractive target for therapeutic genome engineering for the b-hemoglobinopathies. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Science (pre-March 2025) is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
| PLink | https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=pbh&AN=90658805 |
| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1126/science.1242088 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 6 StartPage: 253 Subjects: – SubjectFull: Hemoglobinopathy Type: general – SubjectFull: Erythrocyte membranes Type: general – SubjectFull: Transcription factors Type: general – SubjectFull: Fetus Type: general – SubjectFull: Genetics Type: general – SubjectFull: Chromatin Type: general – SubjectFull: Gene expression Type: general – SubjectFull: B cells Type: general – SubjectFull: Health Type: general Titles: – TitleFull: An Erythroid Enhancer of BCL11A Subject to Genetic Variation Determines Fetal Hemoglobin Level. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Bauer, Daniel E. – PersonEntity: Name: NameFull: Kamran, Sophia C. – PersonEntity: Name: NameFull: Lessard, Samuel – PersonEntity: Name: NameFull: Jian Xu – PersonEntity: Name: NameFull: Yuko Fujiwara – PersonEntity: Name: NameFull: Carrie Lin – PersonEntity: Name: NameFull: Zhen Shao – PersonEntity: Name: NameFull: Canver, Matthew C. – PersonEntity: Name: NameFull: Smith, Elenoe C. – PersonEntity: Name: NameFull: Pinello, Luca – PersonEntity: Name: NameFull: Sabo, Peter J. – PersonEntity: Name: NameFull: Vierstra, Jeff – PersonEntity: Name: NameFull: Voit, Richard A. – PersonEntity: Name: NameFull: Guo-Cheng Yuan – PersonEntity: Name: NameFull: Porteus, Matthew H. – PersonEntity: Name: NameFull: Stamatoyannopoulos, John A. – PersonEntity: Name: NameFull: Lettre, Guillaume – PersonEntity: Name: NameFull: Orkin, Stuart H. IsPartOfRelationships: – BibEntity: Dates: – D: 11 M: 10 Text: 10/11/2013 Type: published Y: 2013 Identifiers: – Type: issn-print Value: 00368075 Numbering: – Type: volume Value: 342 – Type: issue Value: 6155 Titles: – TitleFull: Science (pre-March 2025) Type: main |
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