Proximal promoter elements of the human zeta-globin gene confer embryonic-specific expression on a linked reporter gene in transgenic mice

Pondel, M.D.; Sharpe, Jacqueline A.; Clark, Shawna; Pearson, Lori; Wood, W. G.; Proudfoot, Nick J.

doi:10.1093/nar/24.21.4158

Cited by 7 publications

(3 citation statements)

References 27 publications

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“…We considered the possibility that this pattern of expression might represent an artifact of the ␤-galactosidase reporter gene, since it has been reported that the ␤-galactosidase cassette interferes with the ability of the ␤-globin locus control region to confer position-independent expression (30), and it has been suggested that the ␤-galactosidase sequence may act as a nucleation point for the formation of heterochromatin in definitive erythroid cells (71). However, several groups have shown that a variety of erythroid enhancers, including the ␤-globin locus control region (30,31), the ␣-globin Ϫ40 element (56,70), and the EKLF Ϫ950 promoter (77), can direct expression of ␤-galactosidase to definitive erythroid cells in transgenic mice. Instead, we favor the alternative explanation that the 3.7-kb fragment containing the ϩ40 region exhibits intrinsic specificity for the primitive erythroid lineage.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Regulation of the SCL Locus: Identification of an Enhancer That Targets the Primitive Erythroid Lineage In Vivo

Delabesse

Ogilvy

Chapman

et al. 2005

Molecular and Cellular Biology

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The stem cell leukemia (SCL) gene, also known as TAL-1, encodes a basic helix-loop-helix protein that is essential for the formation of all hematopoietic lineages, including primitive erythropoiesis. Appropriate transcriptional regulation is essential for the biological functions of SCL, and we have previously identified five distinct enhancers which target different subdomains of the normal SCL expression pattern. However, it is not known whether these SCL enhancers also regulate neighboring genes within the SCL locus, and the erythroid expression of SCL remains unexplained. Here, we have quantitated transcripts from SCL and neighboring genes in multiple hematopoietic cell types. Our results show striking coexpression of SCL and its immediate downstream neighbor, MAP17, suggesting that they share regulatory elements. A systematic survey of histone H3 and H4 acetylation throughout the SCL locus in different hematopoietic cell types identified several peaks of histone acetylation between SIL and MAP17, all of which corresponded to previously characterized SCL enhancers or to the MAP17 promoter. Downstream of MAP17 (and 40 kb downstream of SCL exon 1a), an additional peak of acetylation was identified in hematopoietic cells and was found to correlate with expression of SCL but not other neighboring genes. This ؉40 region is conserved in human-dog-mouse-rat sequence comparisons, functions as an erythroid cell-restricted enhancer in vitro, and directs ␤-galactosidase expression to primitive, but not definitive, erythroblasts in transgenic mice. The SCL ؉40 enhancer provides a powerful tool for studying the molecular and cellular biology of the primitive erythroid lineage.

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Section: Discussionmentioning

confidence: 99%

Transcriptional Regulation of the SCL Locus: Identification of an Enhancer That Targets the Primitive Erythroid Lineage In Vivo

Delabesse

Ogilvy

Chapman

et al. 2005

Molecular and Cellular Biology

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“…The pattern of basal transgene expression observed in Tg.AC mice re¯ected the tissue-and development-speci®c expressions of the z-globin gene. Only 67 bp of sequence proximate to the transcription start site was reported to be required to confer the erythroid-speci®c expression of the z-globin gene [13,14]. No apparent previously recognized enhancer sequence was contained within the 78-bp deletion of the z-globin promoter sequence in N 2 nonresponder mice.…”

Section: DI Is Sc Cu Us Ss Si Io On Nmentioning

confidence: 99%

Loss of palindromic symmetry in Tg.AC mice with a nonresponder phenotype

et al. 2001

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The Tg.AC transgenic mouse carries the v‐Ha‐ras oncogene under the control of the ζ‐globin promoter and is currently being used in a short‐term carcinogenesis assay for safety testing of pharmaceuticals. A subset of hemizygous Tg.AC mice was found to be nonresponsive to the tumor promoter 12‐O‐tetradecanoylphorbol‐13‐acetate, which characteristically induces skin papillomas in these mice with repeated dermal applications. We previously showed that responder and nonresponder hemizygous Tg.AC mice carry about 40 copies of transgene but that the nonresponders had lost a 2‐kb BamHI fragment containing the ζ‐globin promoter sequence. The present restriction enzyme and S1 nuclease digestion experiments strongly suggested that the 2‐kb BamHI fragment resulted from the orientation of two transgenes in an inverted repeat formation. Two subsets of nonresponder Tg.AC mice were identified. Restriction enzyme and S1 nuclease digestion experiments suggested that one nonresponder genotype was produced by a large deletion of one or more near complete copies of transgene sequence and the other genotype was produced by a small deletion near the apex of the “head‐to‐head” juncture of the inverted repeat. Polymerase chain reaction amplification, cloning, and sequencing results confirmed the palindromic orientation of transgene in Tg.AC mice. Our results indicated that, despite the presence of multiple copies of transgene in a direct repeat orientation, loss of symmetry in the palindromic array of transgene sequence results in the loss of the responder phenotype in Tg.AC mice. Mol. Carcinog. 30:99–110, 2001. Published 2001 Wiley‐Liss, Inc.

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“…1993). Another study showed that the embryonic specific activation of the ζglobin gene is conferred by the 67 bp ζ -promoter fragment containing only a CACCC and TATA box (Pondel et al . 1996).…”

Section: Introductionmentioning

confidence: 99%

Gene order in human α‐globin locus is required for their temporal specific expressions

et al. 2005

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The human α α α α -globin cluster represents a unique model of transcriptional regulation and provides challenges to the current understanding of interactions between distal and proximal regulatory elements. Although the gene proximal regions are believed to possess almost all the necessary elements for temporal and spatial specificity of gene transcription, it is still not clear whether the relative distance of embryonic ζ ζ ζ ζ -and fetal /adult α α α α -genes to their distal regulatory element α α α α -URE plays any role in transcriptional switching. To investigate the role of gene order in regulating temporal expression, we inverted the entire structure gene region of human α α α α -globin locus in a BAC clone bringing α α α α -genes closest to α α α α -URE and ζ ζ ζ ζ -gene the farthest away. Expression analysis of the reverted locus in transgenic mice showed that α α α α -globin genes, now relocated closer to α α α α -URE, maintained their expression levels through all developmental stages. However, the ζ ζ ζ ζ -globin gene suffered a total loss at both embryonic and fetal /adult stages. It indicates that proximal location of ζ ζ ζ ζ -globin gene to α α α α -URE is necessary for its normal embryonic expression and necessary to prevent embryonic expression of the α α α α -globin gene. We proved that, in the human α α α α -globin gene cluster, the normal order of structural genes relative to α α α α -URE plays a crucial role in the regulation of developmental switching.

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Proximal promoter elements of the human zeta-globin gene confer embryonic-specific expression on a linked reporter gene in transgenic mice

Cited by 7 publications

References 27 publications

Transcriptional Regulation of the SCL Locus: Identification of an Enhancer That Targets the Primitive Erythroid Lineage In Vivo

Transcriptional Regulation of the SCL Locus: Identification of an Enhancer That Targets the Primitive Erythroid Lineage In Vivo

Loss of palindromic symmetry in Tg.AC mice with a nonresponder phenotype

Gene order in human α‐globin locus is required for their temporal specific expressions

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