Affinage

HBB

Hemoglobin subunit beta · UniProt P68871

Length
147 aa
Mass
16.0 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HBB encodes the beta subunit of hemoglobin and is the paradigmatic erythroid-specific gene whose expression is controlled by a hierarchy of cis-elements, chromatin architecture, and erythroid transcription factors (PMID:2992937, PMID:14517543). The promoter requires the TATA box plus a region between -100 and -58 bp for efficient, initiation-site-specific transcription, and as little as 48 bp of 5'-flanking sequence directs correct erythroid-restricted, developmentally timed expression in vivo (PMID:6276753, PMID:2992937); transcription is strongly stimulated in cis by enhancer elements that function in either orientation over long distances (PMID:6277502), and an erythroid stage-selector element couples the locus enhancer to developmental specificity (PMID:3167976). Activation is realized through formation of an erythroid-specific active chromatin hub in which the locus control region physically loops to the active globin promoter (PMID:14517543), a configuration that depends on Nipbl-loaded cohesin (PMID:21454523) and on PRMT1-catalyzed H4R3 dimethylation that recruits PCAF to acetylate H3, licensing LCR-promoter looping and transcription-complex recruitment (PMID:20068219). Developmental gamma-to-beta switching reflects competition of the globin genes for LCR interaction (PMID:1692558) and is governed by the transcription factor EKLF/KLF1, which directly activates beta-globin while indirectly repressing gamma-globin via BCL11A (PMID:8918890, PMID:20676097); the locus is additionally repressible by sequence-specific binding of nuclear ferritin-H to a -150 CAGTGC motif (PMID:11481480) and is tethered to the nuclear periphery through Suv39H/G9a-mediated H3K9 methylation (PMID:24297746). Beta-globin pre-mRNA is excised by stepwise splicing in which IVS1 removal generally precedes IVS2 (PMID:7471214, PMID:6292841), and nonsense or splice-site mutations underlie beta-thalassemia: premature termination codons reduce mRNA accumulation at a nuclear/pre-cytoplasmic step characteristic of surveillance (PMID:3353367, PMID:1557399), while intronic mutations such as IVS2-654 create aberrant splice sites that abolish functional beta-globin and recapitulate human disease in mice (PMID:9490703, PMID:30704988). Beyond erythropoiesis, HBB protein acts as a lung-derived antimetastatic factor through a C-terminal peptide (PMID:27793844) and as a direct cardiac target of aconitine that modulates ABHD5/AMPK signaling and NO scavenging (PMID:38467717).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1982 High

    Defining which promoter elements drive beta-globin transcription established the minimal cis-regulatory architecture of the gene.

    Evidence Deletion mutagenesis of the rabbit beta-globin promoter in HeLa cells with S1 nuclease quantitation

    PMID:6276753

    Open questions at the time
    • Did not identify the trans-acting factors binding the -100/-58 element
    • Tested in non-erythroid HeLa cells, not native erythroid context
  2. 1981 High

    Demonstrating that an enhancer could stimulate beta-globin transcription ~200-fold in cis, orientation- and distance-independently, defined the enhancer concept for the gene.

    Evidence Transient transfection of beta-globin/SV40 recombinants with S1 nuclease and immunofluorescence readouts

    PMID:6277502

    Open questions at the time
    • Used a heterologous SV40 enhancer rather than the native erythroid enhancer
    • Mechanism of long-range action not resolved
  3. 1981 High

    Mapping the co-linear pre-mRNA and the order of intron removal established that beta-globin splicing is stepwise, with IVS1 preceding IVS2.

    Evidence S1 nuclease mapping of endogenous rabbit bone marrow RNA, plus in vitro splicing in HeLa extracts

    PMID:6292841 PMID:7471214

    Open questions at the time
    • Spliceosomal components not identified
    • Determinants of intron order not defined
  4. 1985 High

    Transgenic expression showed minimal 5'-flanking sequence suffices for erythroid-restricted, developmentally correct beta-globin expression, linking promoter elements to tissue specificity in vivo.

    Evidence Pronuclear microinjection transgenic mice with RNA and erythrocyte protein analysis across 20 lines

    PMID:2992937

    Open questions at the time
    • Did not yet incorporate the LCR for high-level expression
    • Trans-acting erythroid factors unidentified
  5. 1990 High

    Establishing that gamma- and beta-globin genes compete for LCR interaction explained the mechanism of developmental switching rather than autonomous gene timing.

    Evidence Transgenic mice with LCR HS fused to single genes versus combined gamma+beta locus fragments

    PMID:1692558

    Open questions at the time
    • Molecular basis of competitive selection not defined
    • Factors enforcing stage specificity not identified
  6. 1996 High

    Identifying EKLF/KLF1 as required for beta transcription and for stabilizing LCR-promoter contact placed a specific transcription factor at the center of gamma/beta competition.

    Evidence EKLF knockout / human beta-locus transgenic mice with single-cell transcription and promoter chromatin analysis

    PMID:8918890

    Open questions at the time
    • Downstream effectors of EKLF not resolved at the time
    • Direct versus indirect repression of gamma not separated
  7. 2003 High

    Direct measurement of chromatin conformation revealed the active chromatin hub, showing LCR and active globin gene physically cluster, with stage-specific gene contacts.

    Evidence Chromosome conformation capture (3C) with DNase I hypersensitivity across developmental stages in mouse and human

    PMID:14517543

    Open questions at the time
    • Did not identify the proteins driving loop formation
    • Causality between looping and transcription not yet established
  8. 2010 High

    Defining PRMT1->H4R3me2->PCAF->H3 acetylation as a requirement for LCR-promoter looping connected a specific histone-modification cascade to chromatin hub formation and transcription.

    Evidence In vitro HAT assay, PCAF Co-IP, PRMT1 knockdown/rescue, ChIP and 3C in MEL erythroid progenitors

    PMID:20068219

    Open questions at the time
    • Recruitment of PRMT1 to the locus not defined
    • Interplay with other locus-bound factors not mapped
  9. 2010 High

    Showing KLF1 controls switching through BCL11A clarified that beta activation and gamma repression are partly separable arms of the same factor's program.

    Evidence shRNA KLF1 knockdown in human and mouse adult erythroid progenitors with qRT-PCR of BCL11A and globins

    PMID:20676097

    Open questions at the time
    • Direct KLF1 binding at BCL11A not shown here
    • Quantitative contribution of direct beta activation versus BCL11A axis unresolved
  10. 2011 High

    Identifying Nipbl-dependent cohesin binding as required for LCR-gene looping added the architectural machinery underpinning the active chromatin hub.

    Evidence ChIP for cohesin/Nipbl, 3C, and Nipbl siRNA in differentiating MEL and primary erythroid cells

    PMID:21454523

    Open questions at the time
    • How cohesin selects the LCR-promoter contact not defined
    • Relationship to PRMT1/PCAF cascade not integrated
  11. 2001 High

    Demonstrating sequence-specific binding and repression by nuclear ferritin-H revealed a negative regulatory input at the beta-globin promoter.

    Evidence EMSA with purified ferritin-H, promoter mutagenesis, and reporter cotransfection with EKLF

    PMID:11481480

    Open questions at the time
    • Physiological conditions triggering ferritin-H repression not defined
    • Role at the endogenous locus not established
  12. 2013 High

    Mapping Suv39H/G9a-dependent H3K9 methylation to nuclear peripheral tethering linked locus positioning to specific chromatin marks.

    Evidence BAC transgenesis, FISH, Suv39H/G9a knockdown, and H3K9me2/3 ChIP

    PMID:24297746

    Open questions at the time
    • Functional consequence of peripheral positioning for transcription not resolved
    • Lamin-association readers not identified
  13. 1992 High

    Localizing the nonsense-mutation defect to a nuclear/pre-cytoplasmic step distinguished beta-thalassemia mRNA loss from cytoplasmic instability, foreshadowing nuclear surveillance.

    Evidence Transfection into ts-Pol II cells with separate assays of transcription, stability, splicing, and polyadenylation; prior allelic series of five nonsense mutations

    PMID:1557399 PMID:3353367

    Open questions at the time
    • Surveillance machinery not molecularly identified in these studies
    • Position-dependence of the effect not fully resolved
  14. 2019 High

    Therapeutic CRISPR/Cas12a disruption of aberrant splice sites in patient HSPCs demonstrated that correcting beta-globin splicing restores functional protein, validating splicing mutations as the disease driver.

    Evidence CRISPR RNP electroporation of patient CD34+ HSPCs, erythroid differentiation, splicing RT-PCR and globin HPLC; gene-targeted IVS2-654 mouse model

    PMID:30704988 PMID:9490703

    Open questions at the time
    • Long-term engraftment and off-target effects not addressed here
    • Generalizability across mutation classes not fully tested
  15. 2020 Medium

    Showing that reducing beta-globin itself triggers ATF4/MYB/BCL11A-dependent gamma-globin re-expression revealed a feedback stress response coupling beta levels to fetal globin.

    Evidence CRISPR HBB knockout in isogenic erythroid precursors with RNA-seq and ATF4 ChIP at the HBS1L-MYB enhancer

    PMID:32755585

    Open questions at the time
    • Single-lab pathway placement
    • Direct versus indirect ATF4 effects on globins not fully separated
  16. 2016 Medium

    Identifying HBB as a lung-derived antimetastatic factor with an active C-terminal peptide established a non-erythroid extracellular function.

    Evidence Peptide mapping of lung factors, in vitro apoptosis assays, and xenograft metastasis models

    PMID:27793844

    Open questions at the time
    • Receptor/mechanism of the Metox peptide not defined
    • Single-lab non-erythroid context
  17. 2024 Medium

    Defining HBB as a direct aconitine target that promotes ABHD5/AMPK binding and NO scavenging linked HBB to cardiotoxicity outside its canonical role.

    Evidence Cell-free AC-HBB binding, HBB overexpression/knockdown in cardiomyocytes, Co-IP with ABHD5 and AMPK, S-nitrosylation measurement

    PMID:38467717

    Open questions at the time
    • Single-lab Co-IP without reciprocal/structural validation
    • Physiological relevance beyond aconitine exposure unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the histone-modification cascade, cohesin architecture, and erythroid transcription factors are mechanistically integrated to nucleate and maintain the active chromatin hub remains unresolved.
  • Order of assembly of PRMT1/PCAF, cohesin, and KLF1 at the locus not established
  • How non-erythroid HBB functions relate to the hemoglobin tetramer not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 3
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-8953854 Metabolism of RNA 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-4839726 Chromatin organization 2
Partners
ABHD5AMPKBCL11ACOHESIN/NIPBLFERRITIN-HKLF1PCAFPRMT1
Complex memberships
active chromatin hub (LCR-beta-globin)

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1981 A 72-bp repeated sequence element in SV40 DNA (transcriptional enhancer) acts in cis to increase beta-globin gene transcription ~200-fold; the element functions in either orientation and at positions up to 1400 bp upstream or 3300 bp downstream of the beta-globin transcription initiation site. Transient transfection of HeLa cells with beta-globin gene-SV40 recombinant plasmids; S1 nuclease hybridization assay; immunofluorescent staining for beta-globin protein Cell High 6277502
1982 Efficient transcription of the rabbit beta-globin gene in vivo requires both the ATA (TATA) box and a region between -100 and -58 bp upstream of the transcription start site; deletion of either region reduces transcript levels ~10-fold, and deletion of the ATA box also abolishes initiation-site specificity. Sequences downstream of the ATA box, including the natural cap site, are dispensable. Deletion mutagenesis of the rabbit beta-globin gene introduced into HeLa cells via SV40-plasmid recombinants; S1 nuclease quantitation of beta-globin transcripts Nature High 6276753
1983 An SV40-globin hybrid transcript is produced and translated in infected monkey cells only when the construct retains a ~500 bp SV40 RNA splicing region; deletion of this splicing region abolishes stable globin transcript accumulation and beta-globin protein production. Construction of SV40-beta-globin recombinant viruses with defined deletions; radioimmunoassay for beta-globin protein; RNA analysis in infected monkey cells Cell Medium 225043
1981 The rabbit beta-globin promoter is recognized and transcripts are correctly spliced when the gene is expressed in Xenopus laevis frog embryos, demonstrating conservation of the basic transcriptional and splicing machinery across vertebrates. Microinjection of rabbit beta-globin gene into fertilized Xenopus eggs; S1 nuclease mapping of transcripts Proceedings of the National Academy of Sciences of the United States of America Medium 6946453
1981 The largest beta-globin pre-mRNA is co-linear with the gene and contains both intervening sequences; splicing proceeds stepwise, with removal of the small intron (IVS1) generally preceding removal of the large intron (IVS2), generating partially spliced intermediates. S1 nuclease mapping of RNA from rabbit bone marrow Cell High 7471214
1982 Human beta-globin pre-mRNA is accurately spliced in vitro by HeLa cell whole-cell extracts; the small intervening sequence is removed precisely, yielding a junction sequence identical to authentic reticulocyte beta-globin mRNA. A transcript terminated upstream of the polyadenylation site is spliced most efficiently, whereas one terminated downstream is not spliced. In vitro splicing assay with HeLa cell extracts; primer extension analysis of splice junctions Nucleic acids research High 6292841
1983 The human beta-globin promoter and coding sequences are transcribed by RNA polymerase III (in addition to Pol II); these Pol III transcripts are polyadenylated, probably spliced, and detectable in bone marrow and reticulocytes. Their 5' boundaries map near an Alu-related Pol III promoter consensus sequence between -235 and the cap site. In vitro transcription with alpha-amanitin sensitivity assay; in vivo RNA analysis in bone marrow and reticulocytes Cell Medium 6194893
1984 Induction of beta-globin gene expression in murine erythroleukemia (MEL) cells requires DNA sequences both 5' and 3' of the translation initiation site; hybrid gene experiments show that the 3' beta-globin sequences (coding region) are sufficient to confer inducibility on heterologous promoters, and nuclear run-on confirms induction is at least partly transcriptional. Introduction of deletion mutants and hybrid genes (beta/gamma, beta/H-2Kbm1) into MEL cells; S1 nuclease analysis before and after differentiation; nuclear run-on transcription assay Cell High 6088069
1983 Induction of the beta-globin gene during MEL cell differentiation results at least in part from increased transcription rate, as shown by nuclear transcription (run-on) experiments; both the intact human beta-globin gene and a hybrid mouse-human beta-globin gene are inducible, indicating the regulatory sequences are conserved between mouse and human. Stable cotransformation of MEL cells; S1 nuclease and primer extension analysis; nuclear transcription run-on experiments Cell High 6572107
1985 Human beta-globin gene expression in transgenic mice is restricted to erythroid lineage cells; constructs with as little as 48 bp of 5'-flanking sequence drive erythroid-specific, temporally correct expression. mRNA transcripts have correct 5' ends and direct beta-globin protein synthesis, and human beta-globin protein is detectable in mature erythrocytes. Pronuclear microinjection to generate transgenic mice; S1 nuclease/primer extension for RNA analysis; reticulocyte lysate translation; protein detection in erythrocytes The EMBO journal High 2992937
1988 A chicken erythroid cell-specific enhancer in the intergenic region between adult beta- and embryonic epsilon-globin genes activates transcription of both; correct developmental stage-specific regulation of beta-globin requires interaction of the beta-globin enhancer with a positive regulatory element (the developmental stage selector element, SSE) within the adult beta-globin promoter. Deletion and substitution mutant analysis in avian erythroid cells; transient transfection assays Cell High 3167976
1988 Premature translation termination (nonsense) mutations in the human beta-globin gene decrease steady-state mRNA levels; this effect is observed for all five nonsense mutations tested (at codons 15, 17, 26, 39, 112) but not for two missense mutations, indicating that the presence of a stop codon per se—regardless of position or type—correlates with reduced mRNA accumulation. Heterologous transfection of cloned beta-globin genes carrying defined point mutations; steady-state mRNA quantitation by S1 nuclease assay Proceedings of the National Academy of Sciences of the United States of America High 3353367
1992 The beta-39 nonsense mutation reduces beta-globin mRNA accumulation at a step prior to cytoplasmic accumulation (i.e., a nuclear/pre-cytoplasmic step); cytoplasmic mRNA stability, splicing accuracy, and polyadenylation are not affected, pointing to a defect in nuclear mRNA metabolism. Transfection into cell lines carrying temperature-sensitive RNA Pol II; analysis of transcription rate, mRNA stability, splicing accuracy, and polyadenylation separately Proceedings of the National Academy of Sciences of the United States of America High 1557399
1990 Human gamma-to-beta globin switching in transgenic mice is restored when both gamma- and beta-globin genes compete together for interaction with the LCR hypersensitive (HS) sequences; when HS sequences are fused individually to either gene alone, high expression is achieved but temporal specificity is lost, demonstrating that developmental switching results from gene competition for LCR interaction. Transgenic mice with LCR HS sequences fused to individual globin genes or combined gamma+beta locus fragments; developmental expression analysis Genes & development High 1692558
1996 EKLF (erythroid Krüppel-like factor) is required for beta-globin gene transcription and for stabilizing LCR-beta-globin promoter interaction; in EKLF knockout mice the beta-globin promoter chromatin structure is altered, beta-gene transcription is absent, and gamma-gene transcription increases reciprocally. This demonstrates EKLF plays a major role in gamma/beta competition. Compound EKLF knockout / human beta-locus transgenic mice; single-cell transcription analysis; chromatin structure analysis at beta-globin promoter Genes & development High 8918890
1988 DNA replication is required for transcriptional activation of the Xenopus beta-globin gene in HeLa cell transfections; replication does not act through covalent template modification or simply by increasing copy number, and only replicating templates are transcribed even when co-transfected with non-replicating templates, indicating a direct mechanistic role for replication in gene activation. Transfection of replicating vs. non-replicating Xenopus beta-globin constructs in HeLa cells; co-transfection experiments; copy number analysis Molecular and cellular biology Medium 2835669
1994 Assembly of the chick beta-globin gene locus into synthetic nuclei using Xenopus egg extracts in an erythroid protein environment recapitulates tissue-specific chromatin structure and long-range promoter-enhancer interaction, leading to beta-globin gene activation; nucleosome-repressed templates can be reactivated by DNA replication in the presence of staged erythroid proteins via chromatin remodeling at the promoter and re-establishment of distal enhancer-promoter communication. Synthetic nuclei reconstitution using Xenopus egg extracts; chromatin assembly; transcription assays with erythroid vs. non-erythroid protein extracts Genes & development High 7958909
1997 Novel intergenic nuclear transcripts span the LCR and intergenic regions of the human beta-globin locus in erythroid cells; transient transfection of a beta-globin gene (epsilon, gamma, or beta) induces transcription of the chromosomal LCR and intergenic regions in nonerythroid cells (transinduction) by a mechanism requiring transcription of the plasmid but not protein expression. The plasmid co-localizes with the endogenous locus as shown by in situ hybridization. Nuclear run-on transcription analysis; transient transfection; fluorescence in situ hybridization (FISH) for co-localization Genes & development Medium 9334315
2001 Nuclear ferritin-H specifically binds the CAGTGC motif at position -153 to -148 bp of the human beta-globin promoter; mutation of this motif reduces binding 20-fold in competition gel-shift assays and abolishes ferritin-H-mediated repression of beta-globin promoter-driven reporter expression in cotransfected cells, demonstrating ferritin-H functions as a sequence-specific repressor of the beta-globin gene. Electrophoretic mobility shift assay (EMSA)/competition gel-shift with K562 nuclear extracts and purified human ferritin-H; site-directed mutagenesis of promoter; reporter gene cotransfection with EKLF and ferritin-H expression vectors in CV-1 cells Proceedings of the National Academy of Sciences of the United States of America High 11481480
2003 An erythroid-specific spatial cluster of cis-regulatory elements (active chromatin hub, ACH) forms around the beta-globin LCR and the active globin gene; the core ACH (HS1-HS6 plus upstream 5'HS-60/-62 and downstream 3'HS1) is developmentally conserved in mice and humans. Individual globin genes switch their physical interaction with this cluster during development correlating with changes in their transcriptional activity; in committed erythroid progenitors prior to beta-globin expression only LCR 5'-side interactions are stably present. Chromosome conformation capture (3C); DNase I hypersensitivity; developmental stage analysis in mouse and human erythroid cells Nature genetics High 14517543
2004 Thalassemia mutations in the 5'UTR of the human beta-globin gene (+10(-T), +22(G>A), +33(C>G), +(40-43)(-AAAC)) reduce steady-state mRNA levels 15-38%; nuclear run-on experiments show that +10(-T) and +33(C>G) reduce the transcription rate (disrupting downstream promoter sequences), while +22(G>A) primarily acts post-transcriptionally; none affect mRNA transport, 3' end processing, or cytoplasmic stability. Stable transfection in MEL cells under LCR control; S1 nuclease/RNA quantitation; nuclear run-on; RNA stability assays; nuclear/cytoplasmic fractionation British journal of haematology High 15009072
2007 An intact HS2 enhancer that recruits RNA Pol II is required for intergenic transcription and histone H3 acetylation and H3K4 methylation between the enhancer and the epsilon-globin target gene; however, intergenic transcription and histone modifications are not sufficient for target gene transcription, which additionally requires initiation at the TATA box of the target gene—indicating intergenic and genic transcription complexes are independent. Chromatin immunoprecipitation (ChIP) for H3 acetylation and H3K4 methylation; model locus with HS2-epsilon-globin in chromatin; enhancer deletion analysis Molecular and cellular biology High 17283048
2010 PRMT1-catalyzed asymmetric dimethylation of H4R3 at the beta-globin locus directly enhances histone H3 acetylation (Lys9/Lys14) in vitro by providing a binding surface for PCAF; these modifications are required for efficient LCR-beta-promoter looping, transcription complex recruitment, and beta-globin transcription. PRMT1 knockdown prevents H3 acetylation, LCR-promoter interaction, and erythroid differentiation, all rescued by re-introduction of PRMT1. In vitro histone acetyltransferase assay with dimethyl-H4R3 substrate; co-immunoprecipitation of PCAF with modified H4R3; shRNA knockdown of PRMT1 in MEL erythroid progenitors; ChIP; 3C for LCR-promoter interaction; rescue experiment with rat PRMT1 Blood High 20068219
2010 KLF1 knockdown in human and mouse adult erythroid progenitors markedly reduces BCL11A expression and increases gamma-globin/beta-globin expression ratios, indicating KLF1 controls globin switching by directly activating beta-globin and indirectly repressing gamma-globin through BCL11A. shRNA knockdown of KLF1 in human and mouse adult erythroid progenitors; quantitative RT-PCR for BCL11A, gamma-globin, and beta-globin Nature genetics High 20676097
2011 Upon erythroid differentiation, cohesin and its loading factor Nipbl bind the beta-globin LCR and the activated globin gene; Nipbl-dependent cohesin binding is required for long-range chromatin interactions between CTCF insulator elements and between the LCR distal enhancer and the target globin gene, the latter being critical for globin gene expression in vivo and in vitro. ChIP for cohesin and Nipbl occupancy; chromosome conformation capture (3C); siRNA knockdown of Nipbl; analysis in differentiating MEL and primary erythroid cells The Journal of biological chemistry High 21454523
2013 Three peripheral targeting regions (PTRs) in the HBB BAC drive nuclear peripheral localization of the beta-globin locus; targeting to both peripheral and pericentric heterochromatin depends on Suv39H-mediated H3K9me3 methylation across hundreds of kilobases around HBB, and peripheral tethering of the endogenous HBB locus additionally requires G9a-mediated H3K9me2 in flanking lamin-associated domains. BAC transgenesis; FISH; siRNA knockdown of Suv39H and G9a; chromatin fractionation; ChIP for H3K9me2/3 The Journal of cell biology High 24297746
1998 Replacement of the murine beta-globin genes with the human betaIVS-2-654 C>T thalassemic gene by gene targeting shows that this mutation causes the same aberrant RNA splicing in mice as in humans; no homozygous mice survive postnatally, and heterozygotes show reduced mouse beta-globin, no human beta-globin, and moderate beta-thalassemia. Homologous recombination gene targeting in mouse embryonic stem cells ('plug and socket' method); RNA splicing analysis; hematological characterization of heterozygous mice Blood High 9490703
2002 A T>G mutation at nucleotide 705 of human beta-globin intron 2 creates an aberrant 5' splice site that dominates over the correct splice sites; at temperatures below 30°C this aberrant splicing is inhibited and correct splicing is restored, demonstrating that temperature is a parameter affecting splice site selection in this thalassemic context. Stable cell lines (HeLa, K562) carrying IVS2-705 or IVS2-745 beta-globin constructs; culture at varying temperatures; RT-PCR analysis of splicing products Nucleic acids research Medium 12409448
1995 The second intron (IVS2) of the human beta-globin gene contains four GATA-1 binding sites, two Oct-1 binding sites, two SATB1 binding sites, and a potential homeobox protein binding site, as identified by DNase I footprinting and EMSA of the entire IVS2. DNase I footprinting of entire beta-globin IVS2; electrophoretic mobility shift assay (EMSA); antibody supershift for GATA-1, NFE-2, YY1, Oct-1 The Journal of biological chemistry Medium 7499351
2019 CRISPR/Cas9 (targeting IVS1-110G>A mutation) and Cas12a/Cpf1 (targeting IVS2-654C>T mutation) RNP complexes achieve high-efficiency disruption of aberrant splice sites in primary CD34+ HSPCs from beta-thalassemia patients; erythroid progeny of edited cells show reversal of aberrant splicing and restoration of beta-globin expression. CRISPR RNP electroporation into primary CD34+ HSPCs; erythroid differentiation; RT-PCR for splicing; globin chain HPLC for beta-globin protein restoration Blood High 30704988
2020 CRISPR-Cas9-mediated reduction of beta-globin in differentiating erythroid precursors is sufficient to induce robust re-expression of gamma-globin; RNA-seq identifies ATF4 as a causal regulator of this stress response—ATF4 binds the HBS1L-MYB intergenic enhancer and regulates MYB, which in turn controls BCL11A and gamma-globin levels. CRISPR-Cas9 knockout of HBB in isogenic erythroid precursors; RNA-seq; ATF4 ChIP at HBS1L-MYB enhancer; quantitation of MYB, BCL11A, and globin expression Cell reports Medium 32755585
2024 HBB (hemoglobin subunit beta) is a direct molecular target of aconitine (AC) in cell-free hemoglobin; AC binding to HBB enhances HBB-ABHD5 and HBB-AMPK binding, leading to decreased HDAC-NT generation and cardiomyocyte death. HBB overexpression exacerbates AC-induced cardiotoxicity while HBB knockdown attenuates cardiomyocyte death. AC-triggered hemolysis releases HBB which scavenges NO, decreasing cardioprotective S-nitrosylation. RNA-seq in DO mice; HBB overexpression and knockdown in cardiomyocytes; cell-free binding assay for AC-HBB interaction; co-immunoprecipitation of HBB with ABHD5 and AMPK; measurement of S-nitrosylation and HDAC-NT Acta pharmacologica Sinica Medium 38467717
2016 The beta subunit of hemoglobin (HBB) acts as a lung-derived antimetastatic factor; a short C-terminal peptide region (Metox) is responsible for activity. HBB and the Metox peptide mediate growth arrest and apoptosis of neuroblastoma and other cancer cell lines in vitro, and Metox administration in xenograft models limits adrenal tumor development and spontaneous lung and bone marrow metastases. HBB2 is produced by alveolar epithelial and endothelial cells and is upregulated in mice bearing undetectable metastases. Peptide mapping/fractionation of lung-derived soluble factors; in vitro viability/apoptosis assays; xenograft mouse models; IHC/expression studies for cellular source Cancer research Medium 27793844
2010 HBB (beta-globin) mRNA and protein are expressed in neurons of the brain and are increased in the perihematomal zone after intracerebral hemorrhage; hemin upregulates HBB mRNA in cultured neurons, and this is reduced by the iron chelator deferoxamine, indicating a role for iron/heme signaling in neuronal HBB regulation. In vivo ICH rat model with time-course; in vitro cultured neurons exposed to hemin ± deferoxamine; qRT-PCR and Western blot; immunolocalization Translational stroke research Low 20563289

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1981 Expression of a beta-globin gene is enhanced by remote SV40 DNA sequences. Cell 1430 6277502
1976 Amplification and characterization of a beta-globin gene synthesized in vitro. Cell 449 61066
2003 The beta-globin nuclear compartment in development and erythroid differentiation. Nature genetics 444 14517543
1984 Nonuniform recombination within the human beta-globin gene cluster. American journal of human genetics 428 6097112
1985 Erythroid-specific expression of human beta-globin genes in transgenic mice. The EMBO journal 367 2992937
2010 KLF1 regulates BCL11A expression and gamma- to beta-globin gene switching. Nature genetics 320 20676097
1997 Characterization of the chicken beta-globin insulator. Proceedings of the National Academy of Sciences of the United States of America 320 9012826
1988 Developmental regulation of beta-globin gene switching. Cell 309 3167976
1997 Intergenic transcription and transinduction of the human beta-globin locus. Genes & development 289 9334315
1990 Human gamma- to beta-globin gene switching in transgenic mice. Genes & development 263 1692558
1981 Isolation of beta-globin-related genes from a human cosmid library. Gene 257 6266915
1982 DNA sequences necessary for transcription of the rabbit beta-globin gene in vivo. Nature 256 6276753
1988 Nonsense mutations in the human beta-globin gene affect mRNA metabolism. Proceedings of the National Academy of Sciences of the United States of America 249 3353367
1983 Beta-globin gene inactivation by DNA translocation in gamma beta-thalassaemia. Nature 229 6318113
1984 DNA sequences required for regulated expression of beta-globin genes in murine erythroleukemia cells. Cell 192 6088069
1979 Precise localization of human beta-globin gene complex on chromosome 11. Proceedings of the National Academy of Sciences of the United States of America 183 291941
1996 The role of EKLF in human beta-globin gene competition. Genes & development 180 8918890
1983 The regulated expression of beta-globin genes introduced into mouse erythroleukemia cells. Cell 159 6572107
1981 Transformation of frog embryos with a rabbit beta-globin gene. Proceedings of the National Academy of Sciences of the United States of America 129 6946453
1979 SV40 recombinants carrying rabbit beta-globin gene coding sequences. Cell 125 225043
1992 Beta-globin nonsense mutation: deficient accumulation of mRNA occurs despite normal cytoplasmic stability. Proceedings of the National Academy of Sciences of the United States of America 124 1557399
1987 Association of thalassaemia intermedia with a beta-globin gene haplotype. British journal of haematology 114 2436649
1979 Introduction and expression of a rabbit beta-globin gene in mouse fibroblasts. Proceedings of the National Academy of Sciences of the United States of America 109 293672
2008 Beta-globin regulation and long-range interactions. Advances in genetics 100 18282504
2010 H4R3 methylation facilitates beta-globin transcription by regulating histone acetyltransferase binding and H3 acetylation. Blood 87 20068219
1984 Evolution of the mammalian beta-globin gene cluster. The Journal of biological chemistry 87 6706976
2013 β-Globin cis-elements determine differential nuclear targeting through epigenetic modifications. The Journal of cell biology 85 24297746
2002 ChIPs of the beta-globin locus: unraveling gene regulation within an active domain. Current opinion in genetics & development 82 11893490
2011 Cohesin mediates chromatin interactions that regulate mammalian β-globin expression. The Journal of biological chemistry 81 21454523
1983 Human beta-globin promoter and coding sequences transcribed by RNA polymerase III. Cell 79 6194893
1997 Characterization of adult alpha- and beta-globin genes in the zebrafish. Blood 76 9002973
1990 Beta-globin locus activation regions: conservation of organization, structure, and function. Proceedings of the National Academy of Sciences of the United States of America 72 2236034
1984 Localization of the beta-globin gene by chromosomal in situ hybridization. American journal of human genetics 72 6587773
2008 Joining the loops: beta-globin gene regulation. IUBMB life 71 18767169
1998 A common human beta globin splicing mutation modeled in mice. Blood 71 9490703
1982 Accurate in vitro splicing of human beta-globin RNA. Nucleic acids research 68 6292841
1993 Regulation of the beta-globin locus. Current opinion in genetics & development 67 8504248
2019 Editing aberrant splice sites efficiently restores β-globin expression in β-thalassemia. Blood 65 30704988
1989 Tarsius delta- and beta-globin genes: conversions, evolution, and systematic implications. The Journal of biological chemistry 62 2491855
1984 The primate psi beta 1 gene. An ancient beta-globin pseudogene. Journal of molecular biology 58 6527389
1998 Recombination breakpoints in the human beta-globin gene cluster. Blood 57 9834248
2008 Epigenetics of beta-globin gene regulation. Mutation research 56 18760288
2002 Reliability of DHPLC in mutational screening of beta-globin (HBB) alleles. Human mutation 52 11857746
1994 Regulated expression of the beta-globin gene locus in synthetic nuclei. Genes & development 51 7958909
2018 Gene correction of HBB mutations in CD34+ hematopoietic stem cells using Cas9 mRNA and ssODN donors. Molecular and cellular pediatrics 46 30430274
2000 Site-specific DNA binding and bending by the Borrelia burgdorferi Hbb protein. Molecular microbiology 45 10931312
1981 A transcription map for the rabbit beta-globin gene. Cell 45 7471214
1980 The beta-globin gene is on the short arm of human chromosome 11. Nature 43 7354859
2016 The Beta Subunit of Hemoglobin (HBB2/HBB) Suppresses Neuroblastoma Growth and Metastasis. Cancer research 38 27793844
2010 Brain alpha- and beta-globin expression after intracerebral hemorrhage. Translational stroke research 38 20563289
2001 An orphaned mammalian beta-globin gene of ancient evolutionary origin. Proceedings of the National Academy of Sciences of the United States of America 38 11158601
2007 Beta-globin intergenic transcription and histone acetylation dependent on an enhancer. Molecular and cellular biology 37 17283048
2020 ATF4 Regulates MYB to Increase γ-Globin in Response to Loss of β-Globin. Cell reports 34 32755585
1993 Beta-thalassemia unlinked to the beta-globin gene in an English family. Blood 34 8101733
1979 DNA fragments of the Mus musculus beta globin haplotypes Hbbs and Hbbd. Proceedings of the National Academy of Sciences of the United States of America 32 286321
2017 A phased SNP-based classification of sickle cell anemia HBB haplotypes. BMC genomics 30 28800727
2001 Specific repression of beta-globin promoter activity by nuclear ferritin. Proceedings of the National Academy of Sciences of the United States of America 30 11481480
2007 Control of beta globin genes. Journal of cellular biochemistry 29 17910027
1985 Structure and organization of the bovine beta-globin genes. Molecular biology and evolution 29 3870874
2010 Comprehensive and efficient HBB mutation analysis for detection of beta-hemoglobinopathies in a pan-ethnic population. American journal of clinical pathology 28 20395516
2004 Thalassaemia mutations within the 5'UTR of the human beta-globin gene disrupt transcription. British journal of haematology 28 15009072
1988 Role for DNA replication in beta-globin gene activation. Molecular and cellular biology 28 2835669
2017 Investigation of mutations in the HBB gene using the 1,000 genomes database. PloS one 27 28379995
1999 Oxygen tension modulates beta-globin switching in embryoid bodies. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 27 9973316
2000 Gene regulation and deregulation: a beta globin perspective. Blood reviews 25 11012251
1984 Modular structure of the beta-globin and the TK promoters. The EMBO journal 24 6096121
2018 Geographical distribution of β-globin gene mutations in Syria. Hematology (Amsterdam, Netherlands) 22 29637841
1991 Variability in beta-globin and HPV DNA amplification by PCR from fixed tissues. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 22 1661900
2005 Developmental regulation of the beta-globin gene locus. Progress in molecular and subcellular biology 21 15881896
2002 Temperature-dependent splicing of beta-globin pre-mRNA. Nucleic acids research 21 12409448
2023 Targeting lncRNA16 by GalNAc-siRNA conjugates facilitates chemotherapeutic sensibilization via the HBB/NDUFAF5/ROS pathway. Science China. Life sciences 18 38155279
2013 Epigenetic modifications and chromosome conformations of the beta globin locus throughout development. Stem cell reviews and reports 17 22374078
2010 Evaluation of real-time PCR targeting hbb gene for Borrelia species identification. Journal of microbiological methods 17 20451566
2009 Clinical and hematological characteristics of uncommon beta-globin variants in Thailand. International journal of hematology 17 19440680
2002 Chromatin structure and transcriptional regulation of the beta-globin locus. Experimental cell research 17 12126952
1987 Selective solubilization of beta-globin oligonucleosomes at low ionic strength. Biochemistry 17 3828304
2018 Genetic and Epigenetic Mechanisms of β-Globin Gene Switching. Biochemistry. Biokhimiia 16 29626925
2013 Distinctive mutation spectrum of the HBB gene in an urban eastern Indian population. Hemoglobin 16 24099628
2024 Bacterial histone HBb from Bdellovibrio bacteriovorus compacts DNA by bending. Nucleic acids research 14 38864377
2017 Epigenetic interplay at the β-globin locus. Biochimica et biophysica acta. Gene regulatory mechanisms 14 28161275
2015 β-Globin Mutations in Egyptian Patients With β-Thalassemia. Laboratory medicine 14 25617386
2010 Mutation analysis of the HBB gene in selected Bangladeshi beta-thalassemic individuals: presence of rare mutations. Genetic testing and molecular biomarkers 14 20406103
2010 Structural polymorphism at LCR and its role in beta-globin gene regulation. Biochimie 14 20466031
2004 The mammalian beta globin origin of DNA replication. Frontiers in bioscience : a journal and virtual library 14 15358579
2020 Hematological Characteristics of β-Globin Gene Mutation -50 (G>A) (HBB: c.-100G>A) Carriers in Mainland China. Hemoglobin 13 32674615
1996 Beta-globin gene haplotype in Hb SC disease. American journal of hematology 13 8756085
2014 β-globin genes: mutation hot-spots in the global thalassemia belt. Hemoglobin 12 25523871
2012 Relationship between beta-globin gene carrier state and insulin resistance. Journal of diabetes and metabolic disorders 11 23497547
2008 Beta-globin LCR and intron elements cooperate and direct spatial reorganization for gene therapy. PLoS genetics 11 18404216
2003 Beta-globin gene cluster haplotypes in the Corsican and Sardinian populations. Human biology 11 15018035
1990 Beta-globin gene cluster haplotypes in Hb C heterozygotes. Hemoglobin 11 2228698
2024 HBB contributes to individualized aconitine-induced cardiotoxicity in mice via interfering with ABHD5/AMPK/HDAC4 axis. Acta pharmacologica Sinica 10 38467717
2016 Total Hemoglobin Mass, Aerobic Capacity, and HBB Gene in Polish Road Cyclists. Journal of strength and conditioning research 10 27050243
1995 Nuclear factor binding sites in human beta globin IVS2. The Journal of biological chemistry 10 7499351
1987 The origin of mutant beta-globin genes in human populations. Acta haematologica 10 3120465
1986 A naturally occurring deletion in the mouse Hbbs beta-globin gene cluster. Proceedings of the National Academy of Sciences of the United States of America 10 3459181
2019 Unusual β-Globin Haplotype Distribution in Newborns from Bengo, Angola. Hemoglobin 9 31394941
2012 β-Globin chain abnormalities with coexisting α-thalassemia mutations. Archives of medical science : AMS 9 23056075
1997 A gene tree for beta-globin sequences from Melanesia. Journal of molecular evolution 9 9071021
2020 Development of gene editing strategies for human β-globin (HBB) gene mutations. Gene 8 31987908

Missed literature

Know a paper Affinage missed for HBB? Flag it for the maintainers and the community.

No submissions yet.