Promoters of the murine embryonic β-like globin genes
            <i>Ey</i>
            and β
            <i>h1</i>
            do not compete for interaction with the β-globin locus control region

Hu, Xiao; Bulger, Michael; Roach, Julia N.; Eszterhas, Susan K.; Olivier, Emmanuel; Bouhassira, Eric E.; Groudine, Mark; Fiering, Steven

doi:10.1073/pnas.0337404100

Cited by 11 publications

(14 citation statements)

References 32 publications

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“…As reported previously, 15 the transcription of ␤h1 was not changed by the deletion of the Ey promoter. Hence, the transcription level of ␤h0 could be compared with that of ␤h1 directly, even on the ⌬Ey allele.…”

Section: Transcription Of Other ␤-Type Globin Genes In the Ey And ␤H1supporting

confidence: 56%

“…Each deleted region roughly measured 1.1 kbp, spanning from 700 bp 5Ј to the transcription start site to near the 3Ј end of exon 2 of each gene. 15 One of the ES clones previously targeted to replace the ␤h1 promoter with neo (⌬␤h1neo) was retargeted with the construct that replaced the Ey promoter with hygro (⌬Eyhy-gro). ES clones were screened for targeting of Ey, and Southern blots were used to identify clones that were targeted on both alleles in cis rather than in trans ( Figure 1B).…”

Section: Production Of the Double Embryonic Gene Promoter Deletion Micementioning

confidence: 99%

“…15 To generate mice with Ey and ␤h1 promoters deleted in cis, embryonic stem cell (ES) clones with the ␤h1 promoter targeted by p␤h1prd-Neo were electroporated with the pEyprd-Hygro construct. ES clones correctly targeted in cis with both promoter replacements were used to generate promoter replacement chimeric mice.…”

Section: Generation Of Ey and ␤H1 Promoter Replacement And Deletion Micementioning

confidence: 99%

“…15 In the current study, the promoters of both major embryonic genes were simultaneously deleted, and the phenotype was analyzed in mice. Results reveal that the deletion of Ey, ␤h1, or both increases ␤major and ␤minor expression in the embryo, consistent with the LCR competition model.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional interference among the murine β-like globin genes

Eszterhas

Pallazzi

et al. 2006

Blood

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Mammalian ␤-globin loci contain multiple genes that are activated at different developmental stages. Studies have suggested that the transcription of one gene in a locus can influence the expression of the other locus genes. The prevalent model to explain this transcriptional interference is that all potentially active genes compete for locus control region (LCR) activity. To investigate the influence of transcription by the murine embryonic genes on transcription of the other ␤-like genes, we generated mice with deletions of the promoter regions of Ey and ␤h1 and measured transcription of the remaining genes. Deletion of the Ey and ␤h1 promoters increased transcription of ␤ma-jor and ␤minor 2-fold to 3-fold during primitive erythropoiesis. Deletion of Ey did not affect ␤h1 nor did deletion of ␤h1 affect Ey, but Ey deletion uniquely activated transcription from ␤h0, a ␤-like globin gene immediately downstream of Ey. Protein analysis showed that ␤h0 encodes a translatable ␤-like globin protein that can pair with alpha globin. The lack of transcriptional interference between Ey and ␤h1 and the gene-specific repression of ␤h0 did not support LCR competition among the embryonic genes and suggested that direct transcriptional interference from Ey suppressed ␤h0. IntroductionThe mammalian ␤-globin loci consist of multiple genes that are activated at different developmental stages in a tissue-specific manner. In the mouse, 2 "embryonic" ␤-like globin genes, Ey and ␤h1, are transcribed at high levels only during primitive erythropoiesis in the embryonic yolk sac. The "adult" expressed ␤-type globin genes-␤-major and ␤-minor-are expressed at low levels in embryos and at high levels during fetal and adult definitive erythropoiesis. This developmental up-regulation of the adult ␤-like globin genes is coincident with the silencing of the embryonic ␤-like globin genes and is hypothesized to be mechanistically related to the silencing of the embryonic genes.Regulatory elements of each ␤-like globin gene include a promoter and associated gene proximal cis-regulatory elements bound by multiple-tissue specific or ubiquitous transcription factors. High-level expression of all the genes at the locus requires a gene distal cis-regulatory element, the locus control region (LCR), which is located 5 to 22 kb upstream of the embryonic Ey gene in the mouse locus (for a review, see Stamatoyannopoulos and Grosveld 1 ). The role, if any, of the LCR in the developmental regulation of individual genes within the locus is unclear.Previous studies of ␤-globin gene regulation in transgenic mice carrying portions of the human ␤-globin locus have suggested that developmental expression of the embryonic and adult genes is regulated through different mechanisms. For the embryonic genes, the developmental silencing is gene autonomous and is achieved through binding or dissociation of specific transcription factors to or from the gene proximal cis-regulatory elements. When directly linked to the LCR, the human embryonic ⑀ is expressed only at embryo...

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Section: Transcription Of Other ␤-Type Globin Genes In the Ey And ␤H1supporting

confidence: 56%

Section: Production Of the Double Embryonic Gene Promoter Deletion Micementioning

confidence: 99%

Section: Generation Of Ey and ␤H1 Promoter Replacement And Deletion Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Transcriptional interference among the murine β-like globin genes

Eszterhas

Pallazzi

et al. 2006

Blood

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“…The ␤-globin gene promoters are the most obvious candidate sequences. As such, we examined histone modifications across ␤-globin loci harboring deletions of the embryonic ␤-globin gene promoters.Targeted deletion of the ⑀y-and ␤h1-globin gene promoters, alone and in combination, has been performed previously 28,29 ( Figure 4A). In agreement with these studies, we find that each promoter deletion eliminates expression of the corresponding ␤-globin gene, but expression of the other globin genes is either not affected (⑀y in the ␤h1 promoter deletion, ␤h1 in the ⑀y promoter deletion), or slightly affected (␤1/␤2 expression in the ⑀y/␤h1 double promoter deletion) ( Figure 4B).…”

mentioning

confidence: 99%

Histone hyperacetylation within the β-globin locus is context-dependent and precedes high-level gene expression

Fromm

Vries²,

Byron

et al. 2009

Blood

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Active gene promoters are associated with covalent histone modifications, such as hyperacetylation, which can modulate chromatin structure and stabilize binding of transcription factors that recognize these modifications. At the ␤-globin locus and several other loci, however, histone hyperacetylation extends beyond the promoter, over tens of kilobases; we term such patterns of histone modifications "hyperacetylated domains." Little is known of either the mechanism by which these domains form or their function. Here, we show that domain formation within the murine ␤-globin locus occurs before either high-level gene expression or erythroid commitment. Analysis of ␤-globin alleles harboring deletions of promoters or the locus control region demonstrates that these sequences are not required for domain formation, suggesting the existence of additional regulatory sequences within the locus. Deletion of embryonic globin gene promoters, however, resulted in the formation of a hyperacetylated domain over these genes in definitive erythroid cells, where they are otherwise inactive. Finally, sequences within ␤-globin domains exhibit hyperacetylation in a context-dependent manner, and domains are maintained when transcriptional elongation is inhibited. These data narrow the range of possible mechanisms by which hyperacetylated domains form. (Blood. 2009;114: 3479-3488) IntroductionA crucial feature of gene activation is the interaction between transcription factors and chromatin. All eukaryotic genomic DNA, with limited exceptions, is packaged with core histones to form chromatin. The fundamental subunit of chromatin is the nucleosome, consisting of approximately 147 bp of DNA wrapped in approximately 1.75 turns about an octamer of core histones; a variable length of linker DNA extends between nucleosomes and can in turn be partially sequestered by interactions with core histone amino-terminal "tail" regions and/or linker histones, such as histone H1. The resulting structure, when observed on low-salt spreads by electron microscopy, has been termed "beads on a string" based on its appearance. 1,2 At physiologically relevant salt concentrations, however, this structure spontaneously condenses, first to a helical array of nucleosomes termed the 30-nm fiber, then through additional levels of higher-order structure, which are not well understood. 3 Nevertheless, this packaging renders the eukaryotic DNA relatively inaccessible to transcription factors. [4][5][6] The transcriptional machinery possesses mechanisms for modulating chromatin structure. One of these is covalent modification of core histones, including acetylation, methylation, phosphorylation, ubiquitylation, SUMOylation, and ADP ribosylation, in short, the gamut of modifications known to occur on cellular proteins. Different modifications can lead to different functional consequences. Histone acetylation is associated with transcriptional activation; indeed, core histones proximal to active gene promoters are universally hyperacetylated. 7,8 Histone methylation can...

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QTLs for murine red blood cell parameters in LG/J and SM/J F2 and advanced intercross lines

et al. 2012

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Red blood cells are essential for oxygen transport and other physiologic processes. Red cell characteristics are typically determined by complete blood counts which measure parameters such as hemoglobin levels and mean corpuscular volumes; these parameters reflect the quality and quantity of red cells in the circulation at any particular moment. To identify the genetic determinants of red cell parameters, we performed genome-wide association analysis on LG/J × SM/J F2 and F34 advanced intercross lines using single nucleotide polymorphism genotyping and a novel algorithm for mapping in the combined populations. We identified significant quantitative trait loci for red cell parameters on chromosomes 6, 7, 8, 10, 12 and 17; our use of advanced intercross lines reduced the quantitative trait loci interval width from 1.6- to 9.4-fold. Using genomic sequences of LG/J and SM/J mice, we identified non-synonymous coding single nucleotide polymorphisms in candidate genes residing within quantitative trait loci and performed sequence alignments and molecular modeling to gauge the potential impact of amino acid substitutions. These results should aid in the identification of genes critical for red cell physiology and metabolism and demonstrate the utility of advanced intercross lines in uncovering genetic determinants of inherited traits.

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Promoters of the murine embryonic β-like globin genes Ey and β h1 do not compete for interaction with the β-globin locus control region

Cited by 11 publications

References 32 publications

Transcriptional interference among the murine β-like globin genes

Transcriptional interference among the murine β-like globin genes

Histone hyperacetylation within the β-globin locus is context-dependent and precedes high-level gene expression

QTLs for murine red blood cell parameters in LG/J and SM/J F2 and advanced intercross lines

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