A major positive regulatory region located far upstream of the human alpha-globin gene locus.

Higgs, Douglas R.; Wood, W. G.; Jarman, Andrew P.; Sharpe, Jacqueline A.; Lida, J.; Pretorius, I M; Ayyub, Helena

doi:10.1101/gad.4.9.1588

Cited by 337 publications

(232 citation statements)

References 59 publications

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“…Lying 30-70 kb upstream of the α-globin genes, four highly conserved elements (multispecies conserved sequences, MCS-R1 to 4) corresponding to erythroid-specific DNase I hypersensitive sites (HS-48, HS-40, HS-33, HS-10, respectively) act as long-range regulatory elements of the α-like globin genes [4, reviewed in 5]. Several approaches like the analysis of interspecific hybrids [6] and stable transfectants [6,7], studies in transgenic mice [6,8] or in a humanized mouse model [9], provided evidence that the major regulatory element of this gene cluster in the human locus is MCS-R2 (which corresponds to HS-40). On their own, the other elements (MCS-R1, 3, 4) seem unable to induce substantial levels of α-globin gene expression.…”

Section: Introductionmentioning

confidence: 99%

Novel large deletions in the human α-globin gene cluster: Clarifying the HS-40 long-range regulatory role in the native chromosome environment

Coelho

Picanço

Seuanes³

et al. 2010

Blood Cells, Molecules, and Diseases

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Section: Introductionmentioning

confidence: 99%

Novel large deletions in the human α-globin gene cluster: Clarifying the HS-40 long-range regulatory role in the native chromosome environment

Coelho

Picanço

Seuanes³

et al. 2010

Blood Cells, Molecules, and Diseases

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“…Using QCP, we identified a site at À48 kb (Fig. 3a) that had not been detected in previous extensive surveys 14 . We confirmed that this site could be visualized with conventional assays (Fig.…”

Section: High-throughout Mapping Of Human Gene Regulatory Regionsmentioning

confidence: 71%

“…ARTICLES control elements of the HBA@ upstream regulatory domain and all major hypersensitive sites previously reported following laborious studies of this region with conventional hypersensitivity assays 14 .…”

Section: High-throughout Mapping Of Human Gene Regulatory Regionsmentioning

confidence: 99%

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High-throughput localization of functional elements by quantitative chromatin profiling

et al. 2004

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Identification of functional, noncoding elements that regulate transcription in the context of complex genomes is a major goal of modern biology. Localization of functionality to specific sequences is a requirement for genetic and computational studies. Here, we describe a generic approach, quantitative chromatin profiling, that uses quantitative analysis of in vivo chromatin structure over entire gene loci to rapidly and precisely localize cis-regulatory sequences and other functional modalities encoded by DNase I hypersensitive sites. To demonstrate the accuracy of this approach, we analyzed B300 kilobases of human genome sequence from diverse gene loci and cleanly delineated functional elements corresponding to a spectrum of classical cis-regulatory activities including enhancers, promoters, locus control regions and insulators as well as novel elements. Systematic, highthroughput identification of functional elements coinciding with DNase I hypersensitive sites will substantially expand our knowledge of transcriptional regulation and should simplify the search for noncoding genetic variation with phenotypic consequences.Understanding the human genome will require comprehensive delineation of functional elements within the 98% of genomic terrain that does not encode protein. In vivo, cis-regulatory modalities colocalize with focal alterations in chromatin structure [1][2][3][4] , and this governs the accessibility of genomic sequences to critical regulatory factors. Exploitation of the close connection between functional elements and chromatin structure should offer a powerful and generic approach for de novo identification of cis-regulatory sequences in the context of complex gene domains.Active regulatory elements within complex genomes are distinguished by pronounced sensitivity to the nonspecific endonuclease DNase I 3-5 when exposed in the context of intact nuclei. DNase I hypersensitive sites are the sine qua non of a diverse spectrum of classical transcriptional and chromosomal regulatory activities including enhancers, promoters, silencers, insulators, boundary elements and locus control regions 1,3,6 . Indeed, in the human genome, many functional elements were first identified as major DNase I hypersensitive sites and only later were found to have specific regulatory roles. Analysis of chromatin structure may enable generic delineation of functional elements across the genome, provided it exhibits direct sequence specificity, quantitative data output that permits automated analysis, and adaptability to a high-throughput format.DNase I hypersensitive sites in native genomic domains have traditionally been localized by an approach relying on Southern transfer followed by indirect end-labeling 5 . Although widely applied, this technique is not quantitative and has numerous technical and resource-related limitations that prevent its application on a genome-wide scale. The major limitations of conventional hypersensitivity assays are the low throughput and the lack of sequence specificity. Conventional So...

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“…A distal major regulatory element located 60 kb upstream, called HS Ϫ40, is required for erythrocyte-specific expression of the human ␣-globin gene in transgenic mice (20). When HS Ϫ40 is added to reporter genes promoted by the proximal 5Ј flanking sequences of the human ␣-globin gene (but not including internal sequences), it enhances expression in transiently transfected erythroid cells (31,36).…”

Section: Discussionmentioning

confidence: 99%

CpG Islands from the α-Globin Gene Cluster Increase Gene Expression in an Integration-Dependent Manner

Shewchuk

Hardison

1997

Molecular and Cellular Biology

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In contrast to other globin genes, the human and rabbit ␣-globin genes are expressed in transfected erythroid and nonerythroid cells in the absence of an enhancer. This enhancer-independent expression of the ␣-globin gene requires extensive sequences not only from the 5 flanking sequence but also from the intragenic region. However, the features of these internal sequences that are responsible for their positive effect are unclear. We tested several possible determinants of this activity. One possibility is that a previously identified array of discrete binding sites for known and potential regulatory proteins within the ␣-globin gene comprise an intragenic enhancer specific for the ␣-globin promoter, but directed rearrangements of the sequences show that this is not the case. Alternatively, the promoter may extend into the gene, with the function of the discrete binding sites being dependent on maintenance of their proper positions and orientations relative to the 5 flanking sequence. However, the positive effects observed in gene fusions do not localize to a discrete region of the ␣-globin gene and the results of internal deletions and point mutations argue against a required role of the targeted discrete binding sites. A third possibility is that the CpG island, which includes both the 5 flanking and intragenic regions associated with the positive activity, may itself have a more general effect on expression in transfected cells. Indeed, we show that the size of the CpG island in constructs correlates with the level of gene expression. Furthermore, the ␣-globin promoter is more active in the context of a previously inactive CpG island than in an A؉T-rich context, showing that the CpG island provides an environment more permissive for expression. These effects are seen only after integration, suggesting a possible mechanism at the level of chromatin structure.

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A major positive regulatory region located far upstream of the human alpha-globin gene locus.

Cited by 337 publications

References 59 publications

Novel large deletions in the human α-globin gene cluster: Clarifying the HS-40 long-range regulatory role in the native chromosome environment

Novel large deletions in the human α-globin gene cluster: Clarifying the HS-40 long-range regulatory role in the native chromosome environment

High-throughput localization of functional elements by quantitative chromatin profiling

CpG Islands from the α-Globin Gene Cluster Increase Gene Expression in an Integration-Dependent Manner

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