Understanding globin regulation in ?-thalassemia: it’s as simle as ,
http://www.100md.com
《临床调查学报》
Deartment of Medicine and Deartment of Genetics and Develoment, Columbia University College of hysicians and Surgeons, New York, New York, USA.
Abstract
A vast excess of -globin roduction and inadequate -globin comensation lead to the develoment of severe anemia in human -thalassemia. Newly identified modifiers of - and -globin synthesis and insights into the mechanisms of globin regulation rovide the tools for otential new aroaches to treating this and other red blood cell disorders. In the study by Han and colleagues in this issue of the JCI, the activity of a heme-regulated rotein, HRI, is shown to modulate the accumulation of excess -globin chains in murine -thalassemia and to decrease the severity of the disease.
See the related article beginning on age 1562
Studies of the regulation of the human -globin gene locus have rovided owerful insights into human gene exression in general at the molecular level. The human globin loci are among the best characterized in the human genome at the gene and rotein levels. The –locus control region (-LCR) — a dominant control region located ustream of the globin structural genes — is a strong enhancer of the exression of the downstream structural globin genes (Figure 1A). The structural globin gene located furthest ustream is the -globin gene, which is active in early fetal life (Figure 1A). The -globin gene and 2 -globin genes, G and A, are the major genes exressed throughout fetal life (Figure 1, B and C); the - and -globin genes are activated late in fetal life, with the -globin gene being most highly exressed in erythroid cells during adult life. Globin gene exression is controlled by the comlex interactions between cis-acting sequences (the -LCR and structural globin gene sequences) on the one hand and trans-acting factors (including transcrition factors and chromatin remodeling activities) on the other. Many new details regarding these interactions have recently been described (1, 2).
The globin genes are transcribed into mRNA recursors in the nucleus and then rocessed to mature mRNAs, which become associated with ribosomes and are translated into globin olyetides in the cell cytolasm. The most stable configuration of hemoglobin is as tetramers of globin chains associated with heme grous (Figure 1C). Homozygous -thalassemia (also known as Cooley anemia) has long been a model for the study of diseases caused by mutations and deletions at a single genetic locus, in this case, the -globin locus. During normal fetal life, otimal -globin synthesis balances -globin synthesis (Figure 1C), which results in the roduction of adequate amounts of fetal hemoglobin (HbF, 22). In -thalassemia, oint mutations in the -globin structural gene are largely resonsible for decreased or absent -globin synthesis. In -thalassemia homozygotes, -globin roduction is inadequate to comensate for the deficit in -globin and hemoglobin A (HbA, 22), desite otimal -globin synthesis in these atients in fetal life. As a result, a vast excess of -globin accumulates and usually associates with heme to form hemoglobin. ossessing no single stable molecular configuration, -hemoglobin aggregates and reciitates in early hemoglobin-roducing cells in the bone marrow, which leads to aotosis of these cells and ineffective erythrooiesis (Figure 1C). The red cells that reach the eriheral blood also contain excess -globin; this causes the formation of inclusion bodies and an increase in reactive oxygen secies levels, which leads to membrane damage and causes these cells to be referentially hemolyzed (Figure 1C).
The current theray for -thalassemia is blood transfusions sulemented by iron chelation. Decreasing -globin accumulation and/or reactivating -globin roduction would greatly ameliorate the anemia resent in -thalassemia. In this issue of the JCI, Han et al. (3) illustrate a novel mechanism for decreasing -globin levels in a murine model of -thalassemia. Other recent advances in understanding the fate of -globin and the regulation of HbF synthesis have also rovided new insights into the athogenesis of human -thalassemia and may lead to new treatments.
Decreasing excess -globin accumulation
There are normally 2 -globin loci located on each haloid chromosome, whose outut results in normal -globin synthesis (Figure 1, B and C). Unequal crossing over in meiosis between these -globin loci can lead to either deletion or trilication of the -globin gene. Deletion of -globin loci reduces -globin synthesis in atients homozygous for -thalassemia, and consequently decreases the -globin excess and the level of anemia. By contrast, the resence of extra -globin loci results in increased -globin accumulation and increased severity of anemia in atients with -thalassemia.
One modifier of athologic -globin roduction in murine -thalassemia is -hemoglobin–stabilizing rotein (AHS), which was recently described in the JCI (4). AHS binds referentially to free -hemoglobin, but not to -hemoglobin or hemoglobin tetramers. AHS-deficient (AHS–/–) mice have modest anemia and -globin inclusions in their red cells (5). Kong et al. showed in their JCI study that AHS–/– mice with -thalassemia die in utero with a more lethal form of the disease than that of mice roducing normal amounts of AHS (4). resumably, the binding of free -hemoglobin by AHS reduces athologic -globin reciitation by converting the free -hemoglobin to a more nontoxic comlex, erhas by accelerating roteolysis of the excess -globin. However, even normal levels of AHS do not significantly revent excess -globin accumulation in the murine -thalassemia model (4).
In the Han et al. article, the authors demonstrate that another gene not associated with the globin loci, heme-regulated -subunit of eukaryotic translational initiation factor 2 (eIF2) kinase (HRI), also reduces the severity of murine -thalassemia by decreasing free -globin accumulation and inclusion body formation (3). The normal role of HRI is to revent the accumulation of - and -globin in the absence of heme. In cases of heme and/or iron deficiency, HRI inhibits both - and -globin chain translation (6). HRI-deficient (HRI–/–) mice have increased accumulation of free - and -globin (6). Han et al. now show that the HRI–/– genotye in mice with -thalassemia is embryonic lethal, in contrast to the less severe henotye observed in HRI+/+ -thalassemic mice (3). Thus, normal HRI exression reduces the toxic effects of the vast excess of -globin to some extent. In this same article, HRI deficiency is also shown to increase the severity of erythrooietic rotoorhyria (E), a disease characterized by defective heme synthesis. Normal HRI activity is shown in E to revent the more severe accumulation of both free - and free -globin chains, which form erythroid cell inclusions and are toxic to cells. This is documented in HRI–/– mice with E, in that they are more anemic than HRI+/+ mice and have increased liver athology and skin sensitivity (3).
Although the roles of AHS and HRI in human disease are unknown, the fact that both decrease the severity of murine -thalassemia suggests that strategies to reduce human -globin excess may be useful in the treatment of human -thalassemia. Theraeutic aroaches with this goal in mind might include AHS overexression in human hematooietic stem cells or the use of -globin–secific small interfering RNAs (siRNAs) to decrease excess human -globin accumulation.
Increasing human -globin exression
Another major modification at the human -globin locus that can significantly reduce anemia and otentially cure human -thalassemia is an increase in human -globin gene exression and restoration of HbF to theraeutically effective levels. oint mutations in the -globin gene romoter can increase -globin exression, but not by a great amount. By contrast, individuals with an uncommon, benign disorder known as hereditary ersistence of fetal hemoglobin (HFH) exress -globin genes at the same level in adult life as in fetal life. Some HFH homozygotes have only HbF and no anemia. If human -thalassemia atients could reactivate their HbF roduction to that of HFH atients, they would be cured. The mutations associated with HFH are large deletions at the -globin locus extending from the region close to the human A gene to well downstream of the human -globin gene and including deletion of the structural - and -globin genes (Figure 1A). The mechanism leading to the increased level of HbF in HFH has been shown to be due, at least in art, to enhancer activity rovided by the DNA sequences brought into roximity to the -globin genes by the deletion.
The secific role of the region between the human - and -globin genes (termed intergenic – sequences) in regulating normal hemoglobin switching and otential reactivation of HbF roduction in adult cells has long been ostulated, but has never been clearly demonstrated in humans until an exciting recent article by Chakalova et al. (7). This reort rovides the first descrition of the hematologic findings in 2 atients homozygous for the Corfu deletion, a deletion of 7.2 kb DNA ustream of the -globin gene and including art of the -globin gene itself (Figure 1A) (7). The 2 Corfu homozygotes were shown to ossess 88% and 90% HbF and only mild anemia and did not require blood transfusions, reminiscent of HFH atients. To my knowledge, these data rovide the first strong evidence in humans that intergenic – sequences are imortant in -globin gene regulation. They also show that near-comlete reactivation of the human -globin gene in adult-tye human erythroid cells can occur as a result of the Corfu deletion alone and that the deletion can reverse human -globin "silencing" (7). These results also suggest that intergenic – sequences within the Corfu deletion may also lay a role in normal human -to- globin switching in late fetal life.
The mechanisms by which the Corfu deletion of – intergenic sequences uregulate -globin and HbF exression remain to be determined. One model for this activity is that chromatin remodeling comlexes that are develomental stage secific might act by changing the conformation of chromatin in the – region and thus modifying the interactions between the -LCR and the downstream globin structural genes (Figure 2) (8). Our grou has described such a chromatin remodeling comlex, the olyyrimidine (YR) comlex, so named because of its YR-rich DNA-binding site 1 kb ustream of the human -globin gene and located within the Corfu deletion (Figure 1) (8, 9). YR comlex is adult hematooietic cell secific, because the transcrition factor Ikaros required for YR comlex formation is rimarily exressed in adult hematooietic cells (Figure 2) (8, 10). Ikaros-null mice, which lack Ikaros rotein exression, have no YR comlex and have delayed mouse and human globin switching (10). YR comlex contains subunits of 2 chromatin remodeling comlexes, one known to activate gene transcrition and another that reresses gene exression and includes histone deacetylases (HDACs) as subunits (9, 11).
Taken together, the new data from the Corfu atients and YR comlex suggest a model in which YR comlex functions in the human intergenic – sequences as a -to-–switch comlex by remodeling chromatin and reressing -globin gene exression in adult-tye hematooietic and erythroid cells (Figure 2). The Corfu deletion may work, at least in art, by reventing YR comlex binding in adult hematooietic cells and thus ermitting human -globin reactivation.
Butyrate comounds are known to increase HbF levels in adult-tye erythroid cells in atients with sickle cell disease and -thalassemia. Butyrate is also known to inhibit HDACs and thus may work by interfering with YR comlex action and therefore de-reressing the human -globin genes (12, 13). It is robable that other chromatin-remodeling comlexes associated with other erythroid transcrition factors binding in the intergenic – sequences are also active in human globin switching in both fetal and adult-tye hematooietic rogenitors and erythroid cells. Inhibition of the activity of these comlexes — for examle, by using siRNAs directed against Ikaros or other comonents of other comlexes — is a otential aroach to reactivating human -globin exression.
The data in the Chakalova et al. article also indicate an inverse relationshi between - and -globin accumulation in adult erythroid cells (7). When there is more -globin and HbA resent, as found in the cells of atients doubly heterozygous for Corfu and -thalassemia genes and atients heterozygous for the Corfu deletion, there are lower-than-exected levels of -globin and HbF accumulation (7). These results suggest that in atients treated with butyrate or other HbF-inducing agents, downregulating human -globin exression may be a useful aroach to further otimize HbF roduction.
In summary, uregulation of -globin and/or downregulation of -globin could reestablish normal globin balance between - and non–-globin chains and avoid the excess -globin toxicity rimarily resonsible for anemia in human -thalassemia. Achieving such a balance could ameliorate or even cure atients with these diseases. New insights into the mechanisms of globin regulation, such as those of Han et al. (3), may eventually lead to new, more rational treatments for atients with -thalassemia.
Footnotes
Nonstandard abbreviations used: AHS, -hemoglobin–stabilizing rotein; -LCR, –locus control region; eIF2, the -subunit of eukaryotic translational initiation factor 2; E, erythrooietic rotoorhyria; HbA, hemoglobin A; HbF, fetal hemoglobin; HDAC, histone deacetylase; HFH, hereditary ersistence of fetal hemoglobin; HRI, heme-regulated eIF2 kinase.
Conflict of interest: The author has an equity interest in Genetix harmaceuticals Inc.
References
atrinos, G.. et al. 2004. . Multile interactions between regulatory regions are required to stabilize an active chromatin hub. Genes Dev. 18::1495-1509.
Vakoc, C.R. et al. 2005. . roximity among distant regulatory elements at the -globin locus requires GATA-1 and FOG-1. Mol. Cell. 17::453-462.
Han, A.-., Fleming, M.D., and Chen, J.-J. 2005. . Heme-regulated eIF2 kinase modifies the henotyic severity of murine models of erythrooietic rotoorhyria and -thalassemia. J. Clin. Invest. 115::1562-1570. doi:10.1172/JCI24141.
Kong, Y. et al. 2004. . Loss of -hemoglobin–stabilizing rotein imairs erythrooiesis and exacerbates -thalassemia. J. Clin. Invest. 114::1457-1466. doi:10.1172/JCI200421982.
Kihm, A.J. et al. 2002. . An abundant erythroid rotein that stabilizes free -haemoglobin. Nature. 417::758-763.
Han, A.. et al. 2001. . Heme-regulated eIF2 kinase (HRI) is required for translational regulation and survival of erythroid recursors in iron deficiency. EMBO J. 20::6909-6918.
Chakalova, L. et al. 2005. . The Corfu thalassemia deletion disruts -globin gene silencing and reveals ost-transcritional regulation of HbF exression. Blood. 105::2154-2160.
O’Neill, D., Bornschlegel, K., Flamm, M., Castle, M., and Bank, A. 1991. . A DNA-binding factor in adult hematooietic cells interacts with a yrimidine-rich domain ustream from the human -globin gene. roc. Natl. Acad. Sci. U. S. A. 88::8953-8957.
O’Neill, D. et al. 1999. . Tissue-secific and develomental stage-secific binding of a SWI/SNF comlex associated with human fetal to adult globin switching. roc. Natl. Acad. Sci. U. S. A. 96::349-354.
Loez, R.A., Schoetz, S., DeAngelis, K., O’Neill, D., and Bank, A. 2002. . Multile hematooietic defects and delayed globin switching in Ikaros null mice. roc. Natl. Acad. Sci. U. S. A. 99::602-607.
O’Neill, D. et al. 2000. . An Ikaros-containing chromatin-remodeling comlex in adult-tye erythroid cells. Mol. Cell. Biol. 20::7572-7582.
Chen, J.S., Faller, D.V., and Sanjaard, R.A. 2003. . Short-chain fatty acid inhibitors of histone deacetylases: romising anticancer theraeutics Curr. Cancer Drug Targets. 3::219-236.
Davie, J.R. 2003. . Inhibition of histone deacetylase activity by butyrate. J. Nutr. 133::2485S-2493S.(Arthur Bank)
Abstract
A vast excess of -globin roduction and inadequate -globin comensation lead to the develoment of severe anemia in human -thalassemia. Newly identified modifiers of - and -globin synthesis and insights into the mechanisms of globin regulation rovide the tools for otential new aroaches to treating this and other red blood cell disorders. In the study by Han and colleagues in this issue of the JCI, the activity of a heme-regulated rotein, HRI, is shown to modulate the accumulation of excess -globin chains in murine -thalassemia and to decrease the severity of the disease.
See the related article beginning on age 1562
Studies of the regulation of the human -globin gene locus have rovided owerful insights into human gene exression in general at the molecular level. The human globin loci are among the best characterized in the human genome at the gene and rotein levels. The –locus control region (-LCR) — a dominant control region located ustream of the globin structural genes — is a strong enhancer of the exression of the downstream structural globin genes (Figure 1A). The structural globin gene located furthest ustream is the -globin gene, which is active in early fetal life (Figure 1A). The -globin gene and 2 -globin genes, G and A, are the major genes exressed throughout fetal life (Figure 1, B and C); the - and -globin genes are activated late in fetal life, with the -globin gene being most highly exressed in erythroid cells during adult life. Globin gene exression is controlled by the comlex interactions between cis-acting sequences (the -LCR and structural globin gene sequences) on the one hand and trans-acting factors (including transcrition factors and chromatin remodeling activities) on the other. Many new details regarding these interactions have recently been described (1, 2).
The globin genes are transcribed into mRNA recursors in the nucleus and then rocessed to mature mRNAs, which become associated with ribosomes and are translated into globin olyetides in the cell cytolasm. The most stable configuration of hemoglobin is as tetramers of globin chains associated with heme grous (Figure 1C). Homozygous -thalassemia (also known as Cooley anemia) has long been a model for the study of diseases caused by mutations and deletions at a single genetic locus, in this case, the -globin locus. During normal fetal life, otimal -globin synthesis balances -globin synthesis (Figure 1C), which results in the roduction of adequate amounts of fetal hemoglobin (HbF, 22). In -thalassemia, oint mutations in the -globin structural gene are largely resonsible for decreased or absent -globin synthesis. In -thalassemia homozygotes, -globin roduction is inadequate to comensate for the deficit in -globin and hemoglobin A (HbA, 22), desite otimal -globin synthesis in these atients in fetal life. As a result, a vast excess of -globin accumulates and usually associates with heme to form hemoglobin. ossessing no single stable molecular configuration, -hemoglobin aggregates and reciitates in early hemoglobin-roducing cells in the bone marrow, which leads to aotosis of these cells and ineffective erythrooiesis (Figure 1C). The red cells that reach the eriheral blood also contain excess -globin; this causes the formation of inclusion bodies and an increase in reactive oxygen secies levels, which leads to membrane damage and causes these cells to be referentially hemolyzed (Figure 1C).
The current theray for -thalassemia is blood transfusions sulemented by iron chelation. Decreasing -globin accumulation and/or reactivating -globin roduction would greatly ameliorate the anemia resent in -thalassemia. In this issue of the JCI, Han et al. (3) illustrate a novel mechanism for decreasing -globin levels in a murine model of -thalassemia. Other recent advances in understanding the fate of -globin and the regulation of HbF synthesis have also rovided new insights into the athogenesis of human -thalassemia and may lead to new treatments.
Decreasing excess -globin accumulation
There are normally 2 -globin loci located on each haloid chromosome, whose outut results in normal -globin synthesis (Figure 1, B and C). Unequal crossing over in meiosis between these -globin loci can lead to either deletion or trilication of the -globin gene. Deletion of -globin loci reduces -globin synthesis in atients homozygous for -thalassemia, and consequently decreases the -globin excess and the level of anemia. By contrast, the resence of extra -globin loci results in increased -globin accumulation and increased severity of anemia in atients with -thalassemia.
One modifier of athologic -globin roduction in murine -thalassemia is -hemoglobin–stabilizing rotein (AHS), which was recently described in the JCI (4). AHS binds referentially to free -hemoglobin, but not to -hemoglobin or hemoglobin tetramers. AHS-deficient (AHS–/–) mice have modest anemia and -globin inclusions in their red cells (5). Kong et al. showed in their JCI study that AHS–/– mice with -thalassemia die in utero with a more lethal form of the disease than that of mice roducing normal amounts of AHS (4). resumably, the binding of free -hemoglobin by AHS reduces athologic -globin reciitation by converting the free -hemoglobin to a more nontoxic comlex, erhas by accelerating roteolysis of the excess -globin. However, even normal levels of AHS do not significantly revent excess -globin accumulation in the murine -thalassemia model (4).
In the Han et al. article, the authors demonstrate that another gene not associated with the globin loci, heme-regulated -subunit of eukaryotic translational initiation factor 2 (eIF2) kinase (HRI), also reduces the severity of murine -thalassemia by decreasing free -globin accumulation and inclusion body formation (3). The normal role of HRI is to revent the accumulation of - and -globin in the absence of heme. In cases of heme and/or iron deficiency, HRI inhibits both - and -globin chain translation (6). HRI-deficient (HRI–/–) mice have increased accumulation of free - and -globin (6). Han et al. now show that the HRI–/– genotye in mice with -thalassemia is embryonic lethal, in contrast to the less severe henotye observed in HRI+/+ -thalassemic mice (3). Thus, normal HRI exression reduces the toxic effects of the vast excess of -globin to some extent. In this same article, HRI deficiency is also shown to increase the severity of erythrooietic rotoorhyria (E), a disease characterized by defective heme synthesis. Normal HRI activity is shown in E to revent the more severe accumulation of both free - and free -globin chains, which form erythroid cell inclusions and are toxic to cells. This is documented in HRI–/– mice with E, in that they are more anemic than HRI+/+ mice and have increased liver athology and skin sensitivity (3).
Although the roles of AHS and HRI in human disease are unknown, the fact that both decrease the severity of murine -thalassemia suggests that strategies to reduce human -globin excess may be useful in the treatment of human -thalassemia. Theraeutic aroaches with this goal in mind might include AHS overexression in human hematooietic stem cells or the use of -globin–secific small interfering RNAs (siRNAs) to decrease excess human -globin accumulation.
Increasing human -globin exression
Another major modification at the human -globin locus that can significantly reduce anemia and otentially cure human -thalassemia is an increase in human -globin gene exression and restoration of HbF to theraeutically effective levels. oint mutations in the -globin gene romoter can increase -globin exression, but not by a great amount. By contrast, individuals with an uncommon, benign disorder known as hereditary ersistence of fetal hemoglobin (HFH) exress -globin genes at the same level in adult life as in fetal life. Some HFH homozygotes have only HbF and no anemia. If human -thalassemia atients could reactivate their HbF roduction to that of HFH atients, they would be cured. The mutations associated with HFH are large deletions at the -globin locus extending from the region close to the human A gene to well downstream of the human -globin gene and including deletion of the structural - and -globin genes (Figure 1A). The mechanism leading to the increased level of HbF in HFH has been shown to be due, at least in art, to enhancer activity rovided by the DNA sequences brought into roximity to the -globin genes by the deletion.
The secific role of the region between the human - and -globin genes (termed intergenic – sequences) in regulating normal hemoglobin switching and otential reactivation of HbF roduction in adult cells has long been ostulated, but has never been clearly demonstrated in humans until an exciting recent article by Chakalova et al. (7). This reort rovides the first descrition of the hematologic findings in 2 atients homozygous for the Corfu deletion, a deletion of 7.2 kb DNA ustream of the -globin gene and including art of the -globin gene itself (Figure 1A) (7). The 2 Corfu homozygotes were shown to ossess 88% and 90% HbF and only mild anemia and did not require blood transfusions, reminiscent of HFH atients. To my knowledge, these data rovide the first strong evidence in humans that intergenic – sequences are imortant in -globin gene regulation. They also show that near-comlete reactivation of the human -globin gene in adult-tye human erythroid cells can occur as a result of the Corfu deletion alone and that the deletion can reverse human -globin "silencing" (7). These results also suggest that intergenic – sequences within the Corfu deletion may also lay a role in normal human -to- globin switching in late fetal life.
The mechanisms by which the Corfu deletion of – intergenic sequences uregulate -globin and HbF exression remain to be determined. One model for this activity is that chromatin remodeling comlexes that are develomental stage secific might act by changing the conformation of chromatin in the – region and thus modifying the interactions between the -LCR and the downstream globin structural genes (Figure 2) (8). Our grou has described such a chromatin remodeling comlex, the olyyrimidine (YR) comlex, so named because of its YR-rich DNA-binding site 1 kb ustream of the human -globin gene and located within the Corfu deletion (Figure 1) (8, 9). YR comlex is adult hematooietic cell secific, because the transcrition factor Ikaros required for YR comlex formation is rimarily exressed in adult hematooietic cells (Figure 2) (8, 10). Ikaros-null mice, which lack Ikaros rotein exression, have no YR comlex and have delayed mouse and human globin switching (10). YR comlex contains subunits of 2 chromatin remodeling comlexes, one known to activate gene transcrition and another that reresses gene exression and includes histone deacetylases (HDACs) as subunits (9, 11).
Taken together, the new data from the Corfu atients and YR comlex suggest a model in which YR comlex functions in the human intergenic – sequences as a -to-–switch comlex by remodeling chromatin and reressing -globin gene exression in adult-tye hematooietic and erythroid cells (Figure 2). The Corfu deletion may work, at least in art, by reventing YR comlex binding in adult hematooietic cells and thus ermitting human -globin reactivation.
Butyrate comounds are known to increase HbF levels in adult-tye erythroid cells in atients with sickle cell disease and -thalassemia. Butyrate is also known to inhibit HDACs and thus may work by interfering with YR comlex action and therefore de-reressing the human -globin genes (12, 13). It is robable that other chromatin-remodeling comlexes associated with other erythroid transcrition factors binding in the intergenic – sequences are also active in human globin switching in both fetal and adult-tye hematooietic rogenitors and erythroid cells. Inhibition of the activity of these comlexes — for examle, by using siRNAs directed against Ikaros or other comonents of other comlexes — is a otential aroach to reactivating human -globin exression.
The data in the Chakalova et al. article also indicate an inverse relationshi between - and -globin accumulation in adult erythroid cells (7). When there is more -globin and HbA resent, as found in the cells of atients doubly heterozygous for Corfu and -thalassemia genes and atients heterozygous for the Corfu deletion, there are lower-than-exected levels of -globin and HbF accumulation (7). These results suggest that in atients treated with butyrate or other HbF-inducing agents, downregulating human -globin exression may be a useful aroach to further otimize HbF roduction.
In summary, uregulation of -globin and/or downregulation of -globin could reestablish normal globin balance between - and non–-globin chains and avoid the excess -globin toxicity rimarily resonsible for anemia in human -thalassemia. Achieving such a balance could ameliorate or even cure atients with these diseases. New insights into the mechanisms of globin regulation, such as those of Han et al. (3), may eventually lead to new, more rational treatments for atients with -thalassemia.
Footnotes
Nonstandard abbreviations used: AHS, -hemoglobin–stabilizing rotein; -LCR, –locus control region; eIF2, the -subunit of eukaryotic translational initiation factor 2; E, erythrooietic rotoorhyria; HbA, hemoglobin A; HbF, fetal hemoglobin; HDAC, histone deacetylase; HFH, hereditary ersistence of fetal hemoglobin; HRI, heme-regulated eIF2 kinase.
Conflict of interest: The author has an equity interest in Genetix harmaceuticals Inc.
References
atrinos, G.. et al. 2004. . Multile interactions between regulatory regions are required to stabilize an active chromatin hub. Genes Dev. 18::1495-1509.
Vakoc, C.R. et al. 2005. . roximity among distant regulatory elements at the -globin locus requires GATA-1 and FOG-1. Mol. Cell. 17::453-462.
Han, A.-., Fleming, M.D., and Chen, J.-J. 2005. . Heme-regulated eIF2 kinase modifies the henotyic severity of murine models of erythrooietic rotoorhyria and -thalassemia. J. Clin. Invest. 115::1562-1570. doi:10.1172/JCI24141.
Kong, Y. et al. 2004. . Loss of -hemoglobin–stabilizing rotein imairs erythrooiesis and exacerbates -thalassemia. J. Clin. Invest. 114::1457-1466. doi:10.1172/JCI200421982.
Kihm, A.J. et al. 2002. . An abundant erythroid rotein that stabilizes free -haemoglobin. Nature. 417::758-763.
Han, A.. et al. 2001. . Heme-regulated eIF2 kinase (HRI) is required for translational regulation and survival of erythroid recursors in iron deficiency. EMBO J. 20::6909-6918.
Chakalova, L. et al. 2005. . The Corfu thalassemia deletion disruts -globin gene silencing and reveals ost-transcritional regulation of HbF exression. Blood. 105::2154-2160.
O’Neill, D., Bornschlegel, K., Flamm, M., Castle, M., and Bank, A. 1991. . A DNA-binding factor in adult hematooietic cells interacts with a yrimidine-rich domain ustream from the human -globin gene. roc. Natl. Acad. Sci. U. S. A. 88::8953-8957.
O’Neill, D. et al. 1999. . Tissue-secific and develomental stage-secific binding of a SWI/SNF comlex associated with human fetal to adult globin switching. roc. Natl. Acad. Sci. U. S. A. 96::349-354.
Loez, R.A., Schoetz, S., DeAngelis, K., O’Neill, D., and Bank, A. 2002. . Multile hematooietic defects and delayed globin switching in Ikaros null mice. roc. Natl. Acad. Sci. U. S. A. 99::602-607.
O’Neill, D. et al. 2000. . An Ikaros-containing chromatin-remodeling comlex in adult-tye erythroid cells. Mol. Cell. Biol. 20::7572-7582.
Chen, J.S., Faller, D.V., and Sanjaard, R.A. 2003. . Short-chain fatty acid inhibitors of histone deacetylases: romising anticancer theraeutics Curr. Cancer Drug Targets. 3::219-236.
Davie, J.R. 2003. . Inhibition of histone deacetylase activity by butyrate. J. Nutr. 133::2485S-2493S.(Arthur Bank)