Cited by 183Hemoglobinopathies and Related DisordersGenomics and Chromatin DynamicsHemoglobin structure and function

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Synergistic regulation of human beta-globin gene switching by locus control region elements HS3 and HS4.

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Bungert, J, Davé, U, Lim, K C, Lieuw, K H, Shavit, J A, Liu, Q, Engel, J D·1995·Genes & Development

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Abstract

Proper tissue- and developmental stage-specific transcriptional control over the five genes of the human beta-globin locus is elicited in part by the locus control region (LCR), but the molecular mechanisms that dictate this determined pattern of gene expression during human development are still controversial. By use of homologous recombination in yeast to generate mutations in the LCR within a yeast artificial chromosome (YAC) bearing the entire human beta-globin gene locus, followed by injection of each of the mutated YACs into murine ova, we addressed the function of LCR hypersensitive site (HS) elements 3 and 4 in human beta-globin gene switching. The experiments revealed a number of unexpected properties that are directly attributable to LCR function. First, deletion of either HS3 or HS4 core elements from an otherwise intact YAC results in catastrophic disruption of globin gene expression at all erythroid developmental stages, despite the presence of all other HS elements in the YAC transgenes. If HS3 is used to replace HS4, gene expression is normal at all developmental stages. Conversely, insertion of the HS4 element in place of HS3 results in significant expression changes at every developmental stage, indicating that individual LCR HS elements play distinct roles in stage-specific beta-type globin gene activation. Although the HS4 duplication leads to alteration in the levels of epsilon- and gamma-globin mRNAs during embryonic erythropoiesis, total beta-type globin mRNA synthesis is balanced, thereby leading to the conclusion that all of the human beta-locus genes are competitively regulated. In summary, the human beta-globin HS elements appear to form a single, synergistic functional entity called the LCR, and HS3 and HS4 appear to be individually indispensable to the integrity of this macromolecular complex.

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Authors: Bungert, J., Davé, U., Lim, K. C., Lieuw, K. H., Shavit, J. A., Liu, Q., & Engel, J. D.
Affiliations: Northwestern University (US)
ORCID: Bungert, J
Davé, U
Shavit, J A
Engel, J D
Venue: Genes & Development
Publisher: Cold Spring Harbor Laboratory
Published: 1995-12-15
Volume: 9
Issue: 24
Pages: 3083-3096
ISSN: 0890-9369 (ISSN-L)
1549-5477
DOI: 10.1101/gad.9.24.3083
OpenAlex: W2050579225
Cited by: 183
References: 63
Citations by year: 2025: 1 · 2024: 1 · 2023: 1 · 2021: 5 · 2019: 2 · 2018: 4 · 2017: 1 · 2015: 1 · 2013: 2 · 2012: 4
Type: posted content
Language: en
Open access: bronze
doi.org
Locations: Genes & Development (publishedVersion)
PubMed (publishedVersion)
Funders: Northwestern University
Harvard University
University of Minnesota
Deutsches Krebsforschungszentrum
Deutsche Forschungsgemeinschaft
National Institutes of Health
National Heart, Lung, and Blood Institute (HL 24415, R01HL024415)
Topics: Health Sciences › Medicine › Genetics (clinical) › Hemoglobinopathies and Related Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
Keywords: locus control region, HS3, hypersensitive sites, erythroid development, stage-specific gene expression, embryonic erythropoiesis, epsilon-globin, gamma-globin, competitive regulation, globin gene expression, yeast artificial chromosomes
MeSH terms: Animals, Base Sequence, Globins, Humans, Mice, Transgenic, Molecular Sequence Data, Mutation, Oligodeoxyribonucleotides, RNA, Messenger, Transcriptional Activation, Polymerase Chain Reaction, Chromosomes, Artificial, Yeast, Gene Expression Regulation, Developmental, Mice

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Synergistic regulation of human beta-globin gene switching by locus control region elements HS3 and HS4.

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