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Title: Genetic dissection of the α-globin super-enhancer in vivo

Abstract

Many genes determining cell identity are regulated by clusters of Mediator-bound enhancer elements collectively referred to as super-enhancers. Furthermore, these super-enhancers have been proposed to manifest higher-order properties important in development and disease. Here we report a comprehensive functional dissection of one of the strongest putative super-enhancers in erythroid cells. By generating a series of mouse models, deleting each of the five regulatory elements of the α-globin super-enhancer individually and in informative combinations, we demonstrate that each constituent enhancer seems to act independently and in an additive fashion with respect to hematological phenotype, gene expression, chromatin structure and chromosome conformation, without clear evidence of synergistic or higher-order effects. This study highlights the importance of functional genetic analyses for the identification of new concepts in transcriptional regulation.

Authors:
 [1]; ORCiD logo [1];  [1];  [1]; ORCiD logo [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [1];  [1];  [3];  [1];  [1];  [1];  [2];  [1] more »;  [1];  [1];  [1] « less
  1. Weatherall Inst. of Molecular Medicine, Oxford (United Kingdom). MRC Molecular Haematology Unit
  2. Weatherall Inst. of Molecular Medicine, Oxford (United Kingdom)
  3. Weatherall Inst. of Molecular Medicine, Oxford (United Kingdom). MRC Molecular Haematology Unit; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Genomics Division
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1379541
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Nature Genetics
Additional Journal Information:
Journal Volume: 48; Journal Issue: 8; Journal ID: ISSN 1061-4036
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; epigenetics; gene regulation

Citation Formats

Hay, Deborah, Hughes, Jim R., Babbs, Christian, Davies, James O. J., Graham, Bryony J., Hanssen, Lars L. P., Kassouf, Mira T., Oudelaar, A. Marieke, Sharpe, Jacqueline A., Suciu, Maria C., Telenius, Jelena, Williams, Ruth, Rode, Christina, Li, Pik-Shan, Pennacchio, Len A., Sloane-Stanley, Jacqueline A., Ayyub, Helena, Butler, Sue, Sauka-Spengler, Tatjana, Gibbons, Richard J., Smith, Andrew J. H., Wood, William G., and Higgs, Douglas R. Genetic dissection of the α-globin super-enhancer in vivo. United States: N. p., 2016. Web. doi:10.1038/ng.3605.
Hay, Deborah, Hughes, Jim R., Babbs, Christian, Davies, James O. J., Graham, Bryony J., Hanssen, Lars L. P., Kassouf, Mira T., Oudelaar, A. Marieke, Sharpe, Jacqueline A., Suciu, Maria C., Telenius, Jelena, Williams, Ruth, Rode, Christina, Li, Pik-Shan, Pennacchio, Len A., Sloane-Stanley, Jacqueline A., Ayyub, Helena, Butler, Sue, Sauka-Spengler, Tatjana, Gibbons, Richard J., Smith, Andrew J. H., Wood, William G., & Higgs, Douglas R. Genetic dissection of the α-globin super-enhancer in vivo. United States. doi:10.1038/ng.3605.
Hay, Deborah, Hughes, Jim R., Babbs, Christian, Davies, James O. J., Graham, Bryony J., Hanssen, Lars L. P., Kassouf, Mira T., Oudelaar, A. Marieke, Sharpe, Jacqueline A., Suciu, Maria C., Telenius, Jelena, Williams, Ruth, Rode, Christina, Li, Pik-Shan, Pennacchio, Len A., Sloane-Stanley, Jacqueline A., Ayyub, Helena, Butler, Sue, Sauka-Spengler, Tatjana, Gibbons, Richard J., Smith, Andrew J. H., Wood, William G., and Higgs, Douglas R. Mon . "Genetic dissection of the α-globin super-enhancer in vivo". United States. doi:10.1038/ng.3605. https://www.osti.gov/servlets/purl/1379541.
@article{osti_1379541,
title = {Genetic dissection of the α-globin super-enhancer in vivo},
author = {Hay, Deborah and Hughes, Jim R. and Babbs, Christian and Davies, James O. J. and Graham, Bryony J. and Hanssen, Lars L. P. and Kassouf, Mira T. and Oudelaar, A. Marieke and Sharpe, Jacqueline A. and Suciu, Maria C. and Telenius, Jelena and Williams, Ruth and Rode, Christina and Li, Pik-Shan and Pennacchio, Len A. and Sloane-Stanley, Jacqueline A. and Ayyub, Helena and Butler, Sue and Sauka-Spengler, Tatjana and Gibbons, Richard J. and Smith, Andrew J. H. and Wood, William G. and Higgs, Douglas R.},
abstractNote = {Many genes determining cell identity are regulated by clusters of Mediator-bound enhancer elements collectively referred to as super-enhancers. Furthermore, these super-enhancers have been proposed to manifest higher-order properties important in development and disease. Here we report a comprehensive functional dissection of one of the strongest putative super-enhancers in erythroid cells. By generating a series of mouse models, deleting each of the five regulatory elements of the α-globin super-enhancer individually and in informative combinations, we demonstrate that each constituent enhancer seems to act independently and in an additive fashion with respect to hematological phenotype, gene expression, chromatin structure and chromosome conformation, without clear evidence of synergistic or higher-order effects. This study highlights the importance of functional genetic analyses for the identification of new concepts in transcriptional regulation.},
doi = {10.1038/ng.3605},
journal = {Nature Genetics},
number = 8,
volume = 48,
place = {United States},
year = {2016},
month = {7}
}

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