Disease relevance of HBB

• We show that both delta383 and delta99 specifically enhance expression of cat for plasmids containing a human adult globin (HBB) promoter, whereas expression of similar constructs using human fetal (A gamma-) globin (HBG1) or simian virus 40 (SV40) promoters is not enhanced [1].
• Further studies demonstrated an inverse correlation between the binding affinity of the BP1 protein for the distal beta-globin silencer sequence and the severity of sickle cell anemia, suggesting a possible role for BP1 in determining the production of hemoglobin S [2].
• An element upstream from the human delta-globin-encoding gene specifically enhances beta-globin reporter gene expression in murine erythroleukemia cells [1].
• We have studied the structure and transcription of a cloned human beta-globin gene from a fetus diagnosed for beta 0 thalassemia [3].
• Beta thalassemia in this area is predominantly the beta zero type with low levels of beta-globin mRNA [4].
• Heterozygosis for beta-globin mutations is a novel risk factor for both hepatic iron accumulation and the progression to fibrosis in patients with CHC [5].

Psychiatry related information on HBB

• The human beta-globin and G gamma-globin genes are expressed at different stages of human development and also show distinct temporal patterns of expression when transferred into the mouse germ line [6].
• Because of the interest in tyrosine hydroxylase as a candidate gene for manic-depressive psychosis and other affective disorders, we carried out family studies to determine the linkage of tyrosine hydroxylase with insulin, beta-globin, D11S12 and Harvey-ras 1, members of a linkage group which has previously been localised to 11p [7].
• In summary, alpha- and beta-globin genes may prove as sensitive, pituitary-specific biomarkers of exposure to estrogenic (and/or anti-androgenic) compounds at critical periods of sex development, whose potential in the assessment of endocrine disrupting events at the HP unit merits further investigation [8].
• METHODS: Hemoglobin-related outcome was examined in 253 patients of the TIME study [9].
• In this study, for determining the influence of different life style on the serum alpha hydroxybutyrate dehydrogenase activity (alpha HBD), we carried out surveys and laboratory studies on the relationships of the nutritional intake, physical activity, cigarette smoking and alcohol consumption of young females with their serum alpha HBD activity [10].

High impact information on HBB

• The active beta-globin locus in fetal liver preferentially contacts transcribed, but not necessarily tissue-specific, loci elsewhere on chromosome 7, whereas the inactive locus in fetal brain contacts different transcriptionally silent loci [11].
• Sickle cell anemia (SCA) is a paradigmatic single gene disorder caused by homozygosity with respect to a unique mutation at the beta-globin locus [12].
• In the human chromosomes, five loci were identified as integration sites, and the beta-globin locus and LINE-1 retrotransposons were frequently targeted [13].
• We conclude that during erythroid differentiation, cis-regulatory DNA elements create a developmentally conserved nuclear compartment dedicated to RNA polymerase II transcription of beta-globin genes [14].
• The beta-globin nuclear compartment in development and erythroid differentiation [14].

Chemical compound and disease context of HBB

• Haemoglobin C, which carries a glutamate-to-lysine mutation in the beta-globin chain, protects West African children against Plasmodium falciparum malaria [15].
• A study of the spectrum of beta-thalassemia mutations in the southern part of the West Bank of the Palestinian Authority revealed the presence of 10 different beta-globin mutations [16].
• To begin this study, we constructed a plasmid containing a neomycin resistance gene, a human beta globin gene, and a wild-type DHFR cDNA, and transfected it into mouse erythroleukemia cells [17].
• MATERIAL AND METHOD: Pre and post transplanted EDTA blood samples from the girl with beta thalassemia/ Hemoglobin E were tested for ABO, Rh and direct antiglobulin test (DAT) using the A-B-AB-D-ctl/ AHG card and the titer of anti-A and anti-B were tested by the conventional tube technique [18].
• The picornavirus replication inhibitors HBB and guanidine in the echovirus-9 system: the significance of viral protein 2C [19].

Biological context of HBB

• We placed this element on a removable cassette adjacent to a human HBB (encoding beta-globin) reporter and generated a transgene whose methylation pattern can be switched in vivo [20].
• Furthermore, our findings strongly indicate that the beta-globin gene cluster lies between the PTH and insulin loci [21].
• The results (i) suggest that hemin induction of K562 cells is mediated at a transcriptional level and (ii) reveal the dissociation of delta- and beta-globin gene expression in K562 cells compared with normal erythroid cells [22].
• Because the PTH, insulin, and beta-globin loci have been localized to the short arm of chromosome 11 (11p) we used DNA polymorphisms adjacent to each of these three loci to determine whether they are genetically linked and to determine their order [21].
• The following order of genes on the short arm of human chromosome 11 (11p) was determined previously: parathyroid hormone (PTH)-the beta-globin gene cluster (HBBC)-HRAS1/insulin [23].

Anatomical context of HBB

• BP1 exhibits regulated expression in the human erythroid cell line MB-02, where its expression decreases upon induction of the beta-globin gene [2].
• Inhibition of beta protein 1 expression enhances beta-globin promoter activity and beta-globin mRNA levels in the human erythroleukemia (K562) cell line [24].
• Haemoglobin beta showed significant decreased expression in ACLs and ATCs; however, in PTC, HBB expressed equal to the normal thyroid gland [25].
• The spontaneous mutation frequencies vary widely, from about 0.04/10(6) cells (sickle cell mutations at the human HBB locus) to 30.8/10(6) cells (HLA-A mutations in T lymphocytes) and are dependent on the locus, the system employed and a number of other factors [26].
• The beta + thalassemic and the normal beta-globin genes were cloned into an SV40-pBR328 vector and introduced into HeLa cells by calcium phosphate coprecipitation [27].

Associations of HBB with chemical compounds

• We have previously shown that a DNA-binding factor specific to adult hematopoietic cells (polypryrimidine-binding factor, PYBF) binds to a pyrimidine-rich region 1 kb upstream from the human delta-globin-encoding gene (HBD) [1].
• 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 [28].
• These data suggest that an endonuclease with preference for UG dinucleotides is involved in the degradation of nonsense-containing and, to a lesser extent, nonsense-free human beta-globin mRNAs in mouse erythroid cells [29].
• Hemoglobin Long Island has two separate amino acid abnormalities of beta-globin structure: an extension of the NH2 terminus by a methionine residue and a histidine-to-proline substitution at the normal second position [30].
• However, we were unable to find any other abnormality at either the AUG initiation codon or in the 56 bases upstream from the adenine-to-cytosine transversion (encompassing most of the 5' untranslated region of the mutant beta-globin mRNA) [30].

Physical interactions of HBB

• In an attempt to define boundary elements that could separate these gene clusters, CTCF-binding sites were searched for at the most distal DNase I-hypersensitive sites (HSs) of the mouse and human beta-globin loci [31].
• Chromatin immunoprecipitation using anti-SATB1 anti-body shows selective binding in vivo in the beta-globin cluster to the hypersensitive site 2 (HS2) in the locus control region (LCR) and to the epsilon-globin promoter [32].
• RNase T1 protection and immunoprecipitation experiments demonstrate that recombinant protein A1 specifically binds the 3'-end regions of both beta-globin and Ad-2 introns [33].
• Strong linkage disequilibrium of a HbE variant with the (AT)9(T)5 repeat in the BP1 binding site upstream of the beta-globin gene in the Thai population [34].
• The concentration of the early firing ori-beta in DNA attached to the matrix decreased in early S phase, while the late firing beta-globin origin remained attached until late S phase [35].

Enzymatic interactions of HBB

• In a patient homozygous for the G gamma A gamma type of HPFH at least 24 kb of DNA in the globin gene region has been deleted to remove most of the gamma-delta intergenic region and the delta and beta globin genes [36].

Regulatory relationships of HBB

• High-mobility group protein 2 may be involved in the locus control region regulation of the beta-globin gene cluster [37].
• Instead, we find that intergenic transcripts of the beta-globin gene cluster are specifically upregulated in Dicer-deficient cells [38].
• 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 [39].
• Our results further indicate that in hematopoietic progenitors, EKLF influences chromatin organization at the human beta-globin locus and is instrumental for human beta-gene potentiation [40].
• In contrast, there were no specific transcripts of beta globin detected in either the control or activin-treated cells [41].

Other interactions of HBB

• Therefore, the gene order on 11p is centromere-PTH-beta-globin-insulin [21].
• Human beta-globin locus control region HS5 contains CTCF- and developmental stage-dependent enhancer-blocking activity in erythroid cells [42].
• A non-BWS translocation breakpoint was more proximal, between HBB and calcitonin-A (CALCA) [43].
• The part of the gene identical to a beta-globin gene shifted to the part identical to the delta-globin gene somewhere in a homologous sequence region between the third nucleotide of the 17th codon and the second nucleotide of the 22nd codon of these two genes [44].
• Thus, the ICR autonomously recapitulated imprinting within the normally nonimprinted transgenic beta-globin gene locus, but the temporal establishment of imprinting methylation differs from that at the endogenous Igf2/H19 locus [45].

Analytical, diagnostic and therapeutic context of HBB

• A better understanding of this mechanism may lay the groundwork for novel gene therapy approaches to inhibit the expression of abnormal structural variants of adult beta globin, such as sickle hemoglobin [24].
• RESULTS: Flow cytometry and fluorescence digital imaging showed about threefold increase in the beta-globin promoter activity of the mutated silencer II construct [24].
• Using electrophoretic mobility shift assay and solid-phase DNase I footprinting methods, we identified a small nuclear protein from K562 cells that binds specifically to the first AT-rich region flanking the hypersensitive site 2 core sequence of the human beta-globin gene locus control region [37].
• Two mutations in the beta-globin poly(A) signal were identified in Israeli patients with beta +-thalassemia by sequence analysis following PCR [46].
• Localization of the beta-globin gene by chromosomal in situ hybridization [47].

References