Cited by 224Genomics and Chromatin DynamicsHemoglobinopathies and Related DisordersHemoglobin structure and function

β-globin Gene Switching and DNase I Sensitivity of the Endogenous β-globin Locus in Mice Do Not Require the Locus Control Region

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Bender, M.A, Bulger, Michael, Close, Jennie, Groudine, Mark·2000·Molecular Cell

Abstract

We have generated mice with a targeted deletion of the beta-globin locus control region (LCR). Mice homozygous for the deletion die early in embryogenesis but can be rescued with a YAC containing the human beta-globin locus. After germline passage, deletion of the LCR leads to a severe reduction in expression of all mouse beta-like globin genes, but no alteration in the developmental specificity of expression. Furthermore, a DNase I-sensitive "open" chromatin conformation of the locus is established and maintained. Thus, the dominant role of the LCR in the native locus is to confer high-level transcription, and elements elsewhere in the locus are sufficient to establish and maintain an open conformation and to confer developmentally regulated globin gene expression.

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  • Previous studies deleting the entire β-globin super-enhancer showed that the β-globin genes remain accessible and marked by histone acetylation.

    “previous studies deleting the entire β-globin SE showed that the β-globin genes remain accessible and marked by histone acetylation;55–57”

    From Super-enhancers include classical enhancers and facilitators to fully activate gene expression (2023) · cites this paper as [55]

    The Discussion reports that mice lacking the β-globin LCR (5′HS 1–6) retain a DNase I–sensitive, open β-globin locus, supporting the accessibility part of the claim. Our copy does not report that the β-globin genes remain marked by histone acetylation; its Discussion mentions histone acetylation only in relation to a different locus, IgH/c-myc. (LLM, conf=0.90)

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  • The mammalian β-globin locus developmental β-globin genes are regulated by a powerful tissue-specific enhancer known as a locus control region (LCR).

    “These models were initially applied to the mammalian β-globin locus, in which the developmental β-globin genes are regulated by a powerful tissue-specific enhancer known as a locus control region (LCR) [254–257].”

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  1. [4]4. Bulger, M ∙ Groudine, M Looping vs. linkingtoward a model for long-distance gene activation Genes Dev. 1999; 13:2465-2477 Crossref Scopus (380) PubMed Google Scholar

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Authors
Bender, M. A., Bulger, M., Close, J., & Groudine, M.
Affiliations
  • University of Washington (US)
  • Fred Hutch Cancer Center (US)
Corresponding author
Groudine, Mark
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2000-02
Volume
5
Issue
2
Pages
387-393
ISSN
1097-2765 (ISSN-L)
OpenAlex
W1982328581
Cited by
224
References
46
Citations by year
2026: 2 · 2024: 3 · 2023: 6 · 2022: 3 · 2021: 2 · 2020: 5 · 2019: 1 · 2018: 4 · 2017: 1 · 2016: 7 · 2015: 3 · 2014: 7 · 2013: 5 · 2012: 3
FWCI
9.77
Type
journal article
Language
en
Open access
Locations
  • Molecular Cell (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health (P30 HD28834, DK54071, DK44746)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
Keywords
beta-globin locus control region, DNase I sensitivity, open chromatin, globin gene expression, embryonic lethality, developmental gene expression, chromatin conformation
MeSH terms
Animals, Chromatin, Deoxyribonuclease I, Globins, Heterozygote, Humans, Mice, Mutant Strains, Thalassemia, Gene Rearrangement, Sequence Deletion, Chromosomes, Artificial, Yeast, Gene Expression Regulation, Developmental, DNA Footprinting, Locus Control Region, Mice

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