Disease relevance of HBE1

• Non-coding transcripts far upstream of the epsilon-globin gene are distinctly expressed in human primary tissues and erythroleukemia cell lines [1].
• These cells were isolated from non-cystic fibrosis subjects and immortalized with HPV18 genes E6 and E7 (ref. 1). HBE1 cells express a homolog of canine TBM (as demonstrated by TBM expression at the transcription and translation level) [2].
• We present here the analysis of a family with a 3,030-bp deletion of sequences upstream of the epsilon globin gene including the most 3' locus control region element and cosegregating beta(0) thalassemia [3].
• Functional studies of embryonic epsilon-globin indicate that individuals with beta thalassemia or sickle cell disease are likely to benefit from therapeutic, transcriptional derepression of its encoding gene [4].
• The data support the hypothesis that Hb Gower-2, assembled from reactivated epsilon globin in individuals with defined hemoglobinopathies and thalassemias, would serve as a physiologically acceptable substitute for deficient or dysfunctional Hb A [5].

High impact information on HBE1

• In three nonerythroid cell lines, "leaky" epsilon-globin transcription occurs exclusively from one of these upstream sites, the -200 cap site [6].
• The human epsilon-globin gene has a number of alternative transcription-initiation sites located upstream of the canonical mRNA cap site [6].
• In three established cell lines derived from adult non-erythroid tissue, low levels of transcription of the epsilon-globin gene occur, but the RNA molecules originate exclusively from one of the upstream sites identified in erythroid cells [7].
• Approximately 10%-15% of epsilon-globin transcripts originate from these upstream sites in both an erythroleukemic cell line and purified erythroblasts from first-trimester human embryos [7].
• Hypomethylation of bone-marrow DNA near both the gamma-globin and epsilon-globin genes was directly demonstrated [8].

Chemical compound and disease context of HBE1

• A plasmid (pSV2neo-epsilon) containing a complete epsilon-globin gene and 2 kilobases (kb) of 5' flanking DNA as well as a neomycin-resistance gene and a simian virus 40 origin of replication was transfected into Bos cells; the compound G418, a neomycin analogue, was used to select transformed cells [9].
• Cell-free extracts prepared from DRBR-1 cells are able to transcribe the epsilon-globin or the adenovirus 2 major late promoter genes at DRB concentrations that eliminate the transcriptional activity of HeLa cell extracts [10].
• The effects of atropine on normal and anomalous A-V pathways were investigated using HBE in 40 cases consisting of 25 subjects without pre-excitation (group I) and 15 cases with WPW syndrome (group II) [11].

Biological context of HBE1

• Dinucleotide repeat polymorphisms at the P1, HBE1 and MYH7 loci [12].
• We describe the complete nucleotide sequence of the human epsilon-globin gene including 387 nucleotides of 5' flanking sequence and 301 nucleotides of 3' flanking sequence [13].
• The sequence data obtained predicted an amino acid sequence that exactly matches a part of human epsilon-globin [14].
• Human embryonic zeta and epsilon globin chains are synthesized in yolk sac-derived primitive erythroid cells, and decrease rapidly during definitive erythropoiesis [15].
• RNA transcribed from the human epsilon globin gene was studied in K562 cells and human embryos of 5-10 weeks gestation [16].

Anatomical context of HBE1

• MUC5B message, to a lesser extent, was also found in the immortalized epithelial cell line HBE1, but not in BEAS-2B cells [17].
• More than half of fetal erythrocytes were positive for zeta and approximately 5% for epsilon globin [15].
• Epsilon globin gene transcripts originating upstream of the mRNA cap site in K562 cells and normal human embryos [16].
• The human epsilon-globin gene is necessary for primitive human erythropoiesis in the yolk sac [18].
• Biochemically transformed cell lines were isolated following transfection of plasmids containing the human epsilon-globin promoter linked to the herpes thymidine kinase coding region (as selectable marker), and an unselected rabbit beta-globin gene [19].

Associations of HBE1 with chemical compounds

• By comparison, hybrid haemoglobins containing either human epsilon-globin or human beta-globin exhibited nearly identical O2-binding properties, both in situ and in vitro, regardless of 2,3-BPG levels or ambient pH [20].
• Concomitant with squamous transformation, there was an increase in SPR1 expression in HTBE, HBE1, and HBE1-C that was reversible by vitamin A. With progression of tumorigenicity, there was a marked reduction in SPR1 expression in BEAS-2B and a total loss of expression in H460 [21].
• Intron transcripts from epsilon-globin, A gamma-globin, delta-globin, and beta-globin were complementary to the loop sequence [22].
• F50 showed a strong dose-dependent inhibitory effect on correctly initiated epsilon-globin gene transcription directed by either unfractionated K562 NE or F175 [23].
• A neomycin resistance gene was cotransfected into these cells, and a neomycin analogue (G418) was used to select cells containing both the neomycin resistance and epsilon-globin genes [24].

Physical interactions of HBE1

• Enhancer-dependent transcription of the epsilon-globin promoter requires promoter-bound GATA-1 and enhancer-bound AP-1/NF-E2 [25].

Regulatory relationships of HBE1

• In luciferase assays FKLF activated the gamma- and epsilon-globin gene promoters, and, to a much lower degree, the beta-globin promoter [26].
• In mice carrying the entire human globin locus, KLF2 also regulates the expression of the human embryonic epsilon-globin gene but not the adult beta-globin gene, suggesting that this developmental-stage-specific role is evolutionarily conserved [27].
• The autonomy of epsilon-globin gene developmental control distinguishes it from the competitive mechanism of regulation of gamma and beta-globin genes, and therefore, suggests that at least two distinct mechanisms function in human hemoglobin switching [28].
• Thus, GATA-1 regulates the response of the epsilon-globin gene to enhancers through a specific site in the promoter and requires enhancer AP-1/NF-E2 binding to transduce the enhancer effect on transcription [25].
• Transient transfection assays also provide evidence that activin A significantly stimulated transcriptional activity of an epsilon globin promoter in K562, but not in the nonerythroid Chinese hamster ovary cells [29].

Other interactions of HBE1

• One site 170 bp upstream of the major beta-globin cap site and a site 1400 bp upstream of the major epsilon-globin cap site are located near putative PolIII promoter sequences and may therefore be transcribed by this enzyme [30].
• Here we show SATB1 family protein induction during early human adult erythroid progenitor cell differentiation concomitant with epsilon-globin expression [31].
• Using primary passage-1 human tracheobronchial epithelial cell cultures and an immortalized human bronchial epithelial cell line, HBE1, we observed that tumor necrosis factor (TNF)-alpha enhanced NF-kappa B transcriptional activity [32].
• ChIP analysis reveals that NF-E2 is associated with the active epsilon-globin promoter, which lacks an NF-E2 binding sequence, in a TATA box and HS2/MARE-dependent fashion [33].
• The nucleosome at the promoter which is altered upon activation is positioned over the transcriptional elements of the epsilon-globin gene, i.e., the TATA, CCAAT, and CACCC elements, and the GATA-1 site at -165 [34].

Analytical, diagnostic and therapeutic context of HBE1

• Molecular cloning of human epsilon-globin gene [14].
• Examination of zeta and epsilon globin expression at the cellular level using dual-color immunofluorescence staining with specific monoclonal antibodies showed that embryonic globin proteins are present in definitive erythroid cells [15].
• With this notion in mind, high-density DNA microarray nylon membrane with colorimetry detection was used to profile the expression of smoke- and hydrogen peroxide-inducible genes in a human bronchial epithelial cell line, HBE1 [35].
• We used chromatin immunoprecipitation and real-time PCR to analyze histone modification and pol II recruitment to the globin locus in human erythroid K562 cells that express the embryonic epsilon-globin gene but not the adult beta-globin gene [36].
• Using cell culture and transgenic mouse model systems, we demonstrate that epsilon-globin mRNA is modestly unstable in immature, transcriptionally active erythroid cells, but that this characteristic has relatively little impact on the accumulation of epsilon-globin mRNA at subsequent stages of terminal differentiation [4].

References