An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level

Daniel E. Bauer; Sophia C. Kamran; Samuel Lessard; Jian Xu; Yuko Fujiwara; Carrie Lin; Zhen Shao; Matthew C. Canver; Elenoe C. Smith; Luca Pinello; Peter J. Sabo; Jeff Vierstra; Richard A. Voit; Guo Cheng Yuan; Matthew H. Porteus; John A. Stamatoyannopoulos; Guillaume Lettre; Stuart H. Orkin

doi:10.1126/science.1242088

An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level

Daniel E. Bauer, Sophia C. Kamran, Samuel Lessard, Jian Xu, Yuko Fujiwara, Carrie Lin, Zhen Shao, Matthew C. Canver, Elenoe C. Smith, Luca Pinello, Peter J. Sabo, Jeff Vierstra, Richard A. Voit, Guo Cheng Yuan, Matthew H. Porteus, John A. Stamatoyannopoulos, Guillaume Lettre, Stuart H. Orkin

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472 Scopus citations

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 β-hemoglobinopathies.

Original language	English (US)
Pages (from-to)	253-257
Number of pages	5
Journal	Science
Volume	342
Issue number	6155
DOIs	https://doi.org/10.1126/science.1242088
State	Published - 2013

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Bauer, D. E., Kamran, S. C., Lessard, S., Xu, J., Fujiwara, Y., Lin, C., Shao, Z., Canver, M. C., Smith, E. C., Pinello, L., Sabo, P. J., Vierstra, J., Voit, R. A., Yuan, G. C., Porteus, M. H., Stamatoyannopoulos, J. A., Lettre, G., & Orkin, S. H. (2013). An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science, 342(6155), 253-257. https://doi.org/10.1126/science.1242088

Bauer, DE, Kamran, SC, Lessard, S, Xu, J, Fujiwara, Y, Lin, C, Shao, Z, Canver, MC, Smith, EC, Pinello, L, Sabo, PJ, Vierstra, J, Voit, RA, Yuan, GC, Porteus, MH, Stamatoyannopoulos, JA, Lettre, G & Orkin, SH 2013, 'An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level', Science, vol. 342, no. 6155, pp. 253-257. https://doi.org/10.1126/science.1242088

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title = "An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level",

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 β-hemoglobinopathies.",

author = "Bauer, {Daniel E.} and Kamran, {Sophia C.} and Samuel Lessard and Jian Xu and Yuko Fujiwara and Carrie Lin and Zhen Shao and Canver, {Matthew C.} and Smith, {Elenoe C.} and Luca Pinello and Sabo, {Peter J.} and Jeff Vierstra and Voit, {Richard A.} and Yuan, {Guo Cheng} and Porteus, {Matthew H.} and Stamatoyannopoulos, {John A.} and Guillaume Lettre and Orkin, {Stuart H.}",

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AU - Kamran, Sophia C.

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AU - Xu, Jian

AU - Fujiwara, Yuko

AU - Lin, Carrie

AU - Shao, Zhen

AU - Canver, Matthew C.

AU - Smith, Elenoe C.

AU - Pinello, Luca

AU - Sabo, Peter J.

AU - Vierstra, Jeff

AU - Voit, Richard A.

AU - Yuan, Guo Cheng

AU - Porteus, Matthew H.

AU - Stamatoyannopoulos, John A.

AU - Lettre, Guillaume

AU - Orkin, Stuart H.

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N2 - 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 β-hemoglobinopathies.

AB - 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 β-hemoglobinopathies.

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An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level

Abstract

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