scholarly journals An evolutionarily ancient mechanism for regulation of hemoglobin expression in vertebrate red cells

Blood ◽  
2020 ◽  
Vol 136 (3) ◽  
pp. 269-278
Author(s):  
Masato Miyata ◽  
Nynke Gillemans ◽  
Dorit Hockman ◽  
Jeroen A. A. Demmers ◽  
Jan-Fang Cheng ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Convergent Evolution ◽  
Gene Locus ◽  
Gene Clusters ◽  
Globin Genes ◽  
Adjacent Gene ◽  
Transport Function ◽  
Specific Expression ◽  
River Lamprey ◽  
Structural And Functional Properties

Abstract The oxygen transport function of hemoglobin (HB) is thought to have arisen ∼500 million years ago, roughly coinciding with the divergence between jawless (Agnatha) and jawed (Gnathostomata) vertebrates. Intriguingly, extant HBs of jawless and jawed vertebrates were shown to have evolved twice, and independently, from different ancestral globin proteins. This raises the question of whether erythroid-specific expression of HB also evolved twice independently. In all jawed vertebrates studied to date, one of the HB gene clusters is linked to the widely expressed NPRL3 gene. Here we show that the nprl3-linked hb locus of a jawless vertebrate, the river lamprey (Lampetra fluviatilis), shares a range of structural and functional properties with the equivalent jawed vertebrate HB locus. Functional analysis demonstrates that an erythroid-specific enhancer is located in intron 7 of lamprey nprl3, which corresponds to the NPRL3 intron 7 MCS-R1 enhancer of jawed vertebrates. Collectively, our findings signify the presence of an nprl3-linked multiglobin gene locus, which contains a remote enhancer that drives globin expression in erythroid cells, before the divergence of jawless and jawed vertebrates. Different globin genes from this ancestral cluster evolved in the current NPRL3-linked HB genes in jawless and jawed vertebrates. This provides an explanation of the enigma of how, in different species, globin genes linked to the same adjacent gene could undergo convergent evolution.

The intricacies of β-globin gene expression

1994 ◽  
Vol 72 (9-10) ◽  
pp. 377-380 ◽  
Author(s):  
Christi Andrin ◽  
Charlotte Spencer
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Gene Locus ◽  
Developmental Regulation ◽  
Globin Gene ◽  
Globin Genes ◽  
Specific Expression ◽  
Complicated Process ◽  
The Individual ◽  
Globin Gene Expression

Gene expression is an extremely complicated process in which several mechanisms are involved. Owing to its developmental and tissue-specific expression, the β-globin gene is an excellent model for studying gene expression. β-Globin gene expression involves an interplay between several different mechanisms. Chromatin structure is thought to be altered by the locus control region (LCR) located far upstream of the β-globin gene locus. As well, multiple transcription factors come into play both in the LCR and in the individual promoters and enhancers of the β-globin genes. The interaction between these then allows for delicate regulation of β-globin gene expression. In the following review the elaborate system of β-globin gene expression will briefly be examined.Key words: β-globin, gene expression, chromatin, GATA-I, NF-E2, developmental regulation.

Human globin gene promoter sequences are sufficient for specific expression of a hybrid gene transfected into tissue culture cells

1987 ◽  
Vol 7 (1) ◽  
pp. 398-402
Author(s):  
T Rutherford ◽  
A W Nienhuis
Keyword(s):  
Gene Expression ◽  
Globin Gene ◽  
Gene Promoter ◽  
Gene Promoters ◽  
Globin Genes ◽  
Specific Expression ◽  
Tissue Specific ◽  
Promoter Sequences ◽  
Erythroleukemia Cells ◽  
Murine Erythroleukemia

The contribution of the human globin gene promoters to tissue-specific transcription was studied by using globin promoters to transcribe the neo (G418 resistance) gene. After transfection into different cell types, neo gene expression was assayed by scoring colony formation in the presence of G418. In K562 human erythroleukemia cells, which express fetal and embryonic globin genes but not the adult beta-globin gene, the neo gene was expressed strongly from a fetal gamma- or embryonic zeta-globin gene promoter but only weakly from the beta promoter. In murine erythroleukemia cells which express the endogenous mouse beta genes, the neo gene was strongly expressed from both beta and gamma promoters. In two nonerythroid cell lines, human HeLa cells and mouse 3T3 fibroblasts, the globin gene promoters did not allow neo gene expression. Globin-neo genes were integrated in the erythroleukemia cell genomes mostly as a single copy per cell and were transcribed from the appropriate globin gene cap site. We conclude that globin gene promoter sequences extending from -373 to +48 base pairs (bp) (relative to the cap site) for the beta gene, -385 to +34 bp for the gamma gene, and -555 to +38 bp for the zeta gene are sufficient for tissue-specific and perhaps developmentally specific transcription.

scholarly journals Expression of the chicken beta-globin gene cluster in mice: correct developmental expression and distributed control.

1995 ◽  
Vol 15 (1) ◽  
pp. 407-414 ◽  
Author(s):  
M M Mason ◽  
E Lee ◽  
H Westphal ◽  
M Reitman
Keyword(s):  
Developmental Stage ◽  
Globin Gene ◽  
Stage Iv ◽  
Gene Clusters ◽  
Developmental Expression ◽  
Single Element ◽  
Globin Genes ◽  
Beta Globin ◽  
Variable Expression ◽  
Hypersensitive Sites

To investigate the regulation of gene clusters, we introduced the entire chicken beta-globin cluster into mice. This 35-kb region includes the four globin genes (rho-beta H-beta A-epsilon), the four upstream hypersensitive sites, and the intergenic beta A/epsilon enhancer. The chicken globins are not arranged in order of developmental expression, which is unlike the case for the human beta-globin cluster, in which gene order plays a role in the regulation of globin expression. Mice carrying the chicken cluster expressed the transgenes with the same developmental patterns as seen in the chicken. Therefore, stage-specific erythroid transcriptional milieus existed before the divergence of birds and mammals and have been conserved since then. Mice bearing the complete cluster except for a deletion removing the beta A/epsilon enhancer displayed markedly reduced expression of the beta H, beta A, and epsilon genes with efficient (but variable) rho expression. Mice carrying the four genes and beta A/epsilon enhancer but without the upstream hypersensitive sites showed reduced expression of rho, beta H, and beta A, with variable expression of epsilon. We conclude that (i) all of the genes (except possibly rho) are under the control of both the upstream hypersensitive sites and the enhancer, (ii) the influence of the control elements can extend beyond the nearest active gene, (iii) a single element (the enhancer) can influence more than one gene in a single developmental stage, (iv) the enhancer can work bidirectionally, and (v) neither the upstream sites (as a group) nor the enhancer showed developmental stage specificity. Thus, the regulation of this cluster is achieved by interaction of two distinct control regions with each of the globin genes.

scholarly journals Loading of DNA-Binding Factors to an Erythroid Enhancer

2000 ◽  
Vol 20 (6) ◽  
pp. 1993-2003 ◽  
Author(s):  
Shau-Ching Wen ◽  
Karim Roder ◽  
Kuang-Yu Hu ◽  
Irene Rombel ◽  
Narender R. Gavva ◽  
...  
Keyword(s):  
Regulatory Element ◽  
K562 Cells ◽  
Globin Genes ◽  
Erythroid Cells ◽  
Binding Studies ◽  
Mobility Shift ◽  
Specific Expression ◽  
Factor Binding ◽  
Globin Promoter

ABSTRACT The HS-40 enhancer is the major cis-acting regulatory element responsible for the developmental stage- and erythroid lineage-specific expression of the human α-like globin genes, the embryonic ζ and the adult α2/α/1. A model has been proposed in which competitive factor binding at one of the HS-40 motifs, 3′-NA, modulates the capability of HS-40 to activate the embryonic ζ-globin promoter. Furthermore, this modulation was thought to be mediated through configurational changes of the HS-40 enhanceosome during development. In this study, we have further investigated the molecular basis of this model. First, human erythroid K562 cells stably integrated with various HS-40 mutants cis linked to a human α-globin promoter-growth hormone hybrid gene were analyzed by genomic footprinting and expression analysis. By the assay, we demonstrate that factors bound at different motifs of HS-40 indeed act in concert to build a fully functional enhanceosome. Thus, modification of factor binding at a single motif could drastically change the configuration and function of the HS-40 enhanceosome. Second, a specific 1-bp, GC→TA mutation in the 3′-NA motif of HS-40, 3′-NA(II), has been shown previously to cause significant derepression of the embryonic ζ-globin promoter activity in erythroid cells. This derepression was hypothesized to be regulated through competitive binding of different nuclear factors, in particular AP1 and NF-E2, to the 3′-NA motif. By gel mobility shift and transient cotransfection assays, we now show that 3′-NA(II) mutation completely abolishes the binding of small MafK homodimer. Surprisingly, NF-E2 as well as AP1 can still bind to the 3′-NA(II) sequence. The association constants of both NF-E2 and AP1 are similar to their interactions with the wild-type 3′-NA motif. However, the 3′-NA(II) mutation causes an approximately twofold reduction of the binding affinity of NF-E2 factor to the 3′-NA motif. This reduction of affinity could be accounted for by a twofold-higher rate of dissociation of the NF-E2–3′-NA(II) complex. Finally, we show by chromatin immunoprecipitation experiments that only binding of NF-E2, not AP1, could be detected in vivo in K562 cells around the HS-40 region. These data exclude a role for AP1 in the developmental regulation of the human α-globin locus via the 3′-NA motif of HS-40 in embryonic/fetal erythroid cells. Furthermore, extrapolation of the in vitro binding studies suggests that factors other than NF-E2, such as the small Maf homodimers, are likely involved in the regulation of the HS-40 function in vivo.

Localization of distal regulatory domains in the megakaryocyte-specific platelet basic protein/platelet factor 4 gene locus

Blood ◽  
2001 ◽  
Vol 98 (3) ◽  
pp. 610-617 ◽  
Author(s):  
Chunyan Zhang ◽  
Michael A. Thornton ◽  
M. Anna Kowalska ◽  
Bruce S. Sachis ◽  
Michael Feldman ◽  
...  
Keyword(s):  
Gene Locus ◽  
Basic Protein ◽  
Regulatory Region ◽  
Platelet Factor 4 ◽  
Specific Gene ◽  
Sufficient Information ◽  
Specific Expression ◽  
Platelet Factor ◽  
High Level

Abstract The genes for the related human (h) chemokines, PBP (platelet basic protein) and PF4 (platelet factor 4), are within 5.3 kilobases (kb) of each other and form a megakaryocyte-specific gene locus. The hypothesis was considered that the PBP and PF4 genes share a common distal regulatory region(s) that leads to their high-level megakaryocyte-specific expression in vivo. This study examined PBP and PF4 expression in transgenic mice using 4 distinct humanPBP/PF4 gene locus constructs. These studies showed that within the region studied there was sufficient information to regulate tissue-specific expression of both hPBP and hPF4. Indeed this region contained sufficient DNA information to lead to expression levels of PBP and PF4 comparable to the homologous mouse genes in a position-independent, copy number–dependent fashion. These studies also indicated that the DNA domains that led to this expression were distinct for the 2 genes; hPBP expression is regulated by a region that is 1.5 to 4.4 kb upstream of that gene. Expression of hPF4 is regulated by a region that is either intergenic between the 2 genes or immediately downstream of the hPF4 gene. Comparison of the available human and mouse sequences shows conserved flanking region domains containing potential megakaryocyte-related transcriptional factor DNA-binding sites. Further analysis of these regulatory regions may identify enhancer domains involved in megakaryopoiesis that may be useful in the selective expression of other genes in megakaryocytes and platelets as a strategy for regulating hemostasis, thrombosis, and inflammation.

scholarly journals Predictable activation of tissue-specific expression from a single gene locus using the pOp/LhG4 transactivation system in Arabidopsis

2004 ◽  
Vol 3 (1) ◽  
pp. 91-101 ◽  
Author(s):  
Célia Baroux ◽  
Robert Blanvillain ◽  
Hazel Betts ◽  
Henri Batoko ◽  
Judith Craft ◽  
...  
Keyword(s):  
Gene Locus ◽  
Single Gene ◽  
Specific Expression ◽  
Tissue Specific ◽  
Tissue Specific Expression

scholarly journals Estrogen-inducible and liver-specific expression of the chicken Very Low Density Apolipoprotein II gene locus in transgenic mice

1993 ◽  
Vol 21 (7) ◽  
pp. 1629-1635 ◽  
Author(s):  
Jan Wijnholds ◽  
Sjaak Philipsen ◽  
Sara Pruzina ◽  
Peter Fraser ◽  
Frank Grosveld ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Gene Locus ◽  
Low Density ◽  
Specific Expression

scholarly journals Developmental switch in the relative expression of the alpha 1- and alpha 2-globin genes in humans and in transgenic mice

Blood ◽  
1992 ◽  
Vol 79 (9) ◽  
pp. 2471-2474 ◽  
Author(s):  
M Albitar ◽  
FE Cash ◽  
C Peschle ◽  
SA Liebhaber
Keyword(s):  
Transgenic Mice ◽  
Globin Gene ◽  
Gene Activation ◽  
Experimental System ◽  
Gene Clusters ◽  
Globin Genes ◽  
Beta Globin ◽  
Relative Expression ◽  
Structural Identity ◽  
Alpha Globin

Abstract Human alpha-globin is encoded by two adjacent genes, alpha 2 and alpha 1. Despite their remarkable level of structural identity, the more 5′ (alpha 2) gene is the major alpha-globin locus in the normal adult, expressed at 2.6-fold higher levels than the adjacent and more 3′ (alpha 1) globin gene. In light of the well-characterized pattern of gene activation in the human alpha- and beta-globin gene clusters during development, we considered the possibility that the relative expression of these two alpha-globin loci might be developmentally controlled. Analysis of human embryonic and early fetal erythroid RNA samples confirmed this possibility; levels of mRNA encoded by the two alpha-globin loci are equal in the embryo and subsequently shift to dominant expression of the alpha 2-globin locus at week 8 in utero. In transgenic mice carrying the entire human alpha-globin cluster (except for the theta gene) we show the same shift from equal expression of the alpha 1- and alpha 2-globin loci at the embryonic stage to predominance of the alpha 2-globin locus in the adult. These data demonstrate a switch in the expression of the two adjacent alpha-globin genes during the embryonic-to-fetal switch in erythroid development and provide an experimental system for its further characterization.

scholarly journals Oxygenation properties and isoform diversity of snake hemoglobins

2015 ◽  
Vol 309 (9) ◽  
pp. R1178-R1191 ◽  
Author(s):  
Jay F. Storz ◽  
Chandrasekhar Natarajan ◽  
Hideaki Moriyama ◽  
Federico G. Hoffmann ◽  
Tobias Wang ◽  
...  
Keyword(s):  
Quaternary Structure ◽  
Experimental Studies ◽  
Integrated Analysis ◽  
South American ◽  
Globin Genes ◽  
Isoform Diversity ◽  
Structural And Functional Properties ◽  
Python Molurus ◽  
Crotalus Durissus ◽  
Allosteric Properties

Available data suggest that snake hemoglobins (Hbs) are characterized by a combination of unusual structural and functional properties relative to the Hbs of other amniote vertebrates, including oxygenation-linked tetramer-dimer dissociation. However, standardized comparative data are lacking for snake Hbs, and the Hb isoform composition of snake red blood cells has not been systematically characterized. Here we present the results of an integrated analysis of snake Hbs and the underlying α- and β-type globin genes to characterize 1) Hb isoform composition of definitive erythrocytes, and 2) the oxygenation properties of isolated isoforms as well as composite hemolysates. We used species from three families as subjects for experimental studies of Hb function: South American rattlesnake, Crotalus durissus (Viperidae); Indian python, Python molurus (Pythonidae); and yellow-bellied sea snake, Pelamis platura (Elapidae). We analyzed allosteric properties of snake Hbs in terms of the Monod-Wyman-Changeux model and Adair four-step thermodynamic model. Hbs from each of the three species exhibited high intrinsic O2 affinities, low cooperativities, small Bohr factors in the absence of phosphates, and high sensitivities to ATP. Oxygenation properties of the snake Hbs could be explained entirely by allosteric transitions in the quaternary structure of intact tetramers, suggesting that ligation-dependent dissociation of Hb tetramers into αβ-dimers is not a universal feature of snake Hbs. Surprisingly, the major Hb isoform of the South American rattlesnake is homologous to the minor HbD of other amniotes and, contrary to the pattern of Hb isoform differentiation in birds and turtles, exhibits a lower O2 affinity than the HbA isoform.

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