Deletion of the mouse α-globin regulatory element (HS −26) has an unexpectedly mild phenotype
Open accessAbstract
Natural deletions of the region upstream of the human α-globin gene cluster, together with expression studies in cell lines and transgenic mice, identified a single element (HS −40) as necessary and perhaps sufficient for high-level expression of the α-globin genes. A similar element occupies the corresponding position upstream of the mouse (m) α-globin genes (mHS −26) and was thought to have similar functional properties. We knocked out mHS −26 by homologous recombination and observed the surprising result that instead of the expected severe α-thalassemia phenotype, the mice had a mild disease. Transcription levels of the mouse genes were reduced by about 50%, but homozygotes were healthy, with normal hemoglobin levels and only mild decreases in mean corpuscular volume and mean corpuscular hemoglobin. These results may indicate differences in the regulation of the α-globin clusters in mice and humans or that additionalcis-acting elements remain to be characterized in one or both clusters.
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Sample sizes were chosen with a view to detecting a 25% reduction in haemoglobin.
“Sample sized were chosen with a view to detecting a 25% reduction in haemoglobin; smaller confirmatory datasets were obtained where the analysis of phenotype had already been reported (as for R2 and R3 deletions14, 19.”
From Genetic dissection of the α-globin super-enhancer in vivo (2016) · cites this paper as [19]
The Cytologic and hematologic analysis section describes how haemoglobin was measured, and the Results report haemoglobin findings, but neither states how sample sizes were chosen. Searches for a 25% reduction, sample-size planning, and a power calculation found no passage addressing the claimed detection target. The paper’s finding of essentially normal haemoglobin in untreated knockout mice does not establish what reduction the citing authors planned to detect. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThe α-globin genes are regulated by four conserved erythroid-specific enhancers (R1-R4) and a mouse specific element (Rm) located 14-38 kb upstream of the promoters.
“We have shown that the α-globin genes are regulated by four conserved erythroid-specific enhancers (R1-R4) and a mouse specific element (Rm) located 14-38 kb upstream of the promoters15–17.”
From Tissue-specific CTCF-cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo (2017) · cites this paper as [16]
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Cites
VISTA : visualizing global DNA sequence alignments of arbitrary length
Mayor, C., Brudno, M., Schwartz, J. R., Poliakov, A., Rubin, E. M., Frazer, K. A., Pachter, L. S., & Dubchak, I. L. (2000) · Bioinformatics · doi:10.1093/bioinformatics/16.11.1046 · Cited by 1,017 · see citing works
Hematopoietic Commitment During Embryonic Stem Cell Differentiation in Culture
Keller, G. M., Kennedy, M. A., Papayannopoulou, T., & Wiles, M. V. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.1.473 · Cited by 874 · see citing works
Shivdasani, R. A., Rosenblatt, M., Zucker‐Franklin, D., Jackson, C. W., Hunt, P., Saris, C. J. M., & Orkin, S. H. (1995) · Cell · doi:10.1016/0092-8674(95)90531-6 · Cited by 687 · see citing works
Production of Homozygous Mutant ES Cells with a Single Targeting Construct
Mortensen, R. M., Conner, D. A., Chao, S., Geisterfer-Lowrance, A. A. T., & Seidman, J. G. (1992) · Molecular and Cellular Biology · doi:10.1128/mcb.12.5.2391 · Cited by 415 · see citing works
A major positive regulatory region located far upstream of the human alpha-globin gene locus.Preprint
Higgs, D. R., Wood, W. G., Jarman, A. P., Sharpe, J. A., Lida, J., Pretorius, I., & Ayyub, H. (1990) · Genes & Development · doi:10.1101/gad.4.9.1588 · Cited by 335 · see citing works
Self-citationFiering, S., Epner, E. M., Robinson, K. M., Zhuang, Y., Telling, A., Hu, M., Martin, D. I. K., Enver, T., Ley, T. J., & Groudine, M. T. (1995) · Genes & Development · doi:10.1101/gad.9.18.2203 · Cited by 334 · see citing works
Improved reporter strain for monitoring Cre recombinase-mediated DNA excisions in mice
Mao, X., Fujiwara, Y., & Orkin, S. H. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.9.5037 · Cited by 332 · see citing works
Bender, M. A., Bulger, M., Close, J., & Groudine, M. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)80433-5 · Cited by 224 · see citing works
Erythropoiesis and globin gene expression in mice lacking the transcription factor NF-E2.
Shivdasani, R. A., & Orkin, S. H. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.19.8690 · Cited by 204 · see citing works
Epner, E., Reik, A., Cimbora, D., Telling, A., Bender, M. A., Fiering, S., Enver, T., Martin, D. I. K., Kennedy, M., Keller, G., et al. (1998) · Molecular Cell · doi:10.1016/s1097-2765(00)80144-6 · Cited by 183 · see citing works
Characterization of the Major Regulatory Element Upstream of the Human a-Globin Gene Cluster
Jarman, A. P., Wood, W. G., Sharpe, J. A., Gourdon, G., Ayyub, H., & Higgs, D. R. (1991) · Molecular and Cellular Biology · doi:10.1128/mcb.11.9.4679-4689.1991 · Cited by 171 · see citing works
Self-citationChromo-domain proteins: linking chromatin structure to epigenetic regulation
Cavalli, G., & Paro, R. (1998) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(98)80011-2 · Cited by 169 · see citing works
Reik, A., Telling, A., Zitnik, G., Cimbora, D., Epner, E., & Groudine, M. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.10.5992 · Cited by 163 · see citing works
Flint, J. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.4.371 · Cited by 161 · see citing works
Dependence of Globin Gene Expression in Mouse Erythroleukemia Cells on the NF-E2 Heterodimer
Kotkow, K. J., & Orkin, S. H. (1995) · Molecular and Cellular Biology · doi:10.1128/mcb.15.8.4640 · Cited by 147 · see citing works
The relationship between chromosome structure and function at a human telomeric region
Flint, J., Thomas, K., Micklem, G., et al. (1997) · Nature Genetics · doi:10.1038/ng0397-252 · Cited by 146 · see citing works
Activation by locus control regions?
Grosveld, F. G. (1999) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(99)80023-9 · Cited by 143 · see citing works
Lu, S. J., Rowan, S., Bani, M. R., & Ben‐David, Y. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.18.8398 · Cited by 128 · see citing works
Characterization of the major regulatory element upstream of the human alpha-globin gene cluster.
Jarman, A. P., Wood, W. G., Sharpe, J. A., Gourdon, G., Ayyub, H., & Higgs, D. R. (1991) · Molecular and Cellular Biology · doi:10.1128/mcb.11.9.4679 · Cited by 106 · see citing works
Self-citationDo LCRs Open Chromatin Domains?
Higgs, D. R. (1998) · Cell · doi:10.1016/s0092-8674(00)81761-4 · Cited by 98 · see citing works
Self-citationSimple and efficient production of embryonic stem cell-embryo chimeras by coculture.
Wood, S. A., Pascoe, W. S., Schmidt, C., Kemler, R., Evans, M. J., & Allen, N. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.10.4582 · Cited by 98 · see citing works
Daniels, R. J. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.4.339 · Cited by 94 · see citing works
Craddock, C., Vyas, P., Sharpe, J. A., Ayyub, H., Wood, W. G., & Higgs, D. R. (1995) · The EMBO Journal · doi:10.1002/j.1460-2075.1995.tb07161.x · Cited by 93 · see citing works
Self-citationLethal thalassemia after insertional disruption of the mouse major adult beta-globin gene.
Shehee, W. R., Oliver, P., & Smithies, O. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.8.3177 · Cited by 81 · see citing works
Understanding alpha globin gene expression: a step towards effective gene therapy.
Higgs, D. R., Sharpe, J. A., & Wg, W. (1998) · PubMed · Cited by 76 · see citing works
Self-citationAnalysis of the human alpha globin upstream regulatory element (HS‐40) in transgenic mice.
Sharpe, J. A., Chan‐Thomas, P. S., Lida, J., Ayyub, H., Wood, W. G., & Higgs, D. R. (1992) · The EMBO Journal · doi:10.1002/j.1460-2075.1992.tb05558.x · Cited by 70 · see citing works
Self-citationBender, M. A., Roach, J. N., Halow, J. M., Close, J., Alami, R., Bouhassira, E. E., Groudine, M. T., & Fiering, S. (2001) · Blood · doi:10.1182/blood.v98.7.2022 · Cited by 66 · see citing works
Analysis of the human alpha-globin gene cluster in transgenic mice.
Sharpe, J. A., Wells, D. J., Whitelaw, E., Vyas, P., Higgs, D. R., & Wood, W. G. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.23.11262 · Cited by 65 · see citing works
Self-citationBernet, A., Sabatier, S., Picketts, D., Ouazana, R., Morlé, F., Higgs, D. R., & Godet, J. (1995) · Blood · doi:10.1182/blood.v86.3.1202.1202 · Cited by 50 · see citing works
Self-citationSpivak, J. L., Toretti, D., & Dickerman, H. W. (1973) · Blood · doi:10.1182/blood.v42.2.257.257 · Cited by 41 · see citing works
Inherited thrombotic disorders: An update
Florell, S. R., & Rodgers, G. M. (1997) · American Journal of Hematology · doi:10.1002/(sici)1096-8652(199701)54:1 · Cited by 41 · see citing works
Mouse ζ- and α-Globin Genes: Embryonic Survival, α-Thalassemia, and Genetic Background Effects
Leder, A., Daugherty, C., Whitney, B., & Leder, P. (1997) · Blood · doi:10.1182/blood.v90.3.1275 · Cited by 31 · see citing works
Vassilopoulos, G., Navas, P. A., Skarpidi, E., Peterson, K. R., Lowrey, C. H., Papayannopoulou, T., & Stamatoyannopoulos, G. (1999) · Blood · doi:10.1182/blood.v93.2.703 · Cited by 30 · see citing works
Sharpe, J., Summerhill, R., Vyas, P., et al. (1993) · Blood · doi:10.1182/blood.v82.5.1666.1666 · Cited by 29 · see citing works
Self-citationFeng, D.-X., Liu, D., Huang, Y., et al. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.251550598 · Cited by 28 · see citing works
The mouse alpha-globin locus regulatory element
Gourdon, G., Sharpe, J., Higgs, D. R., & Wood, W. (1995) · Blood · doi:10.1182/blood.v86.2.766.bloodjournal862766 · Cited by 27 · see citing works
Self-citationLocalization and Characterization of the Mouse α-Globin Locus Control Region
Kielman, M. F., Smits, R., & Bernini, L. F. (1994) · Genomics · doi:10.1006/geno.1994.1289 · Cited by 26 · see citing works
Kielman, M. F., Smits, R., Hof, I. H., & Bernini, L. F. (1996) · Genomics · doi:10.1006/geno.1996.0128 · Cited by 18 · see citing works
Espéret, C., Sabatier, S., Deville, M., Ouazana, R., Bouhassira, E. E., Godet, J., Morlé, F., & Bernet, A. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m001757200 · Cited by 13 · see citing works
Vassilopoulos, G., Navas, P. A., Skarpidi, E., et al. (1999) · Blood · doi:10.1182/blood.v93.2.703.402k07_703_712 · Cited by 4 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- Bouhassira EE, Kielman MF, Gilman J, et al. Properties of the mouse ␣-globin HS Ϫ26: rela- tionship to HS Ϫ40, the major enhancer of human ␣-globin gene expression. Am J Hematol. 1997; 54:30-39.
- Bender MA, Roach JN, Halow J, et al. Targeted deletion of 5ЈHS1 and 5ЈHS4 of the -globin locus control region reveals additive activity of the DNase I hypersensitive sites. Blood. 2001;98: 2022-2027.
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Schoenfelder, S., Furlan-Magaril, M., Mifsud, B., Tavares-Cadete, F., Sugar, R., Javierre, B.-M., Nagano, T., Katsman, Y., Sakthidevi, M., Wingett, S. W., et al. (2015) · Genome Research · doi:10.1101/gr.185272.114 · Cited by 460 · see citing works
Genetic dissection of the α-globin super-enhancer in vivo
Hay, D., Hughes, J. R., Babbs, C., Davies, J. O. J., Graham, B. J., Hanssen, L. L. P., Kassouf, M. T., Oudelaar, A. M., Sharpe, J. A., Suciu, M. C., et al. (2016) · Nature Genetics · doi:10.1038/ng.3605 · Cited by 385 · see citing works
Self-citationMultiplexed analysis of chromosome conformation at vastly improved sensitivity
Davies, J. O. J., Telenius, J. M., McGowan, S. J., Roberts, N. A., Taylor, S., Higgs, D. R., & Hughes, J. R. (2016) · Nature Methods · doi:10.1038/nmeth.3664 · Cited by 268 · see citing works
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Hanssen, L. L. P., Kassouf, M. T., Oudelaar, A. M., Biggs, D., Preece, C., Downes, D. J., Gosden, M., Sharpe, J. A., Sloane-Stanley, J. A., Hughes, J. R., et al. (2017) · Nature Cell Biology · doi:10.1038/ncb3573 · Cited by 219 · see citing works
Self-citationAnguita, E., Hughes, J., Heyworth, C., Blobel, G. A., Wood, W. G., & Higgs, D. R. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600274 · Cited by 207 · see citing works
Self-citation
- Authors
- Anguita, E., Sharpe, J. A., Sloane-Stanley, J. A., Tufarelli, C., Higgs, D. R., & Wood, W. G.
- Affiliations
- University of Oxford (GB)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2002-11-15
- Volume
- 100
- Issue
- 10
- Pages
- 3450-3456
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2019944065
- Cited by
- 58
- References
- 40
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2021: 1 · 2020: 1 · 2018: 1 · 2017: 4 · 2016: 3 · 2015: 3 · 2014: 2 · 2013: 2 · 2012: 4
- FWCI
- 1.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Leicester Research Archive (University of Leicester) (submittedVersion)
- Funders
- Wellcome Trust
- Topics
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- alpha-globin gene cluster, alpha-thalassemia, gene knockout, cis-regulatory elements, transcriptional regulation, hemoglobin levels, mean corpuscular volume, human-mouse comparison
- MeSH terms
- Animals, Cell Line, Chromosome Deletion, Genes, Regulator, Multigene Family, Globins, Humans, Phenotype, RNA, Messenger, Down-Regulation, Mutagenesis, alpha-Thalassemia, Mice, Knockout, Mice
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