The CACCC box is duplicated in the β globin gene promoter of humans and other mammals. While the ... more The CACCC box is duplicated in the β globin gene promoter of humans and other mammals. While the function of the proximal element as a binding site for EKLF has already been well established, the role of the distal element remains unclear The distal CACCC box has been previously reported not to bind EKLF in vitro. A minor role of the distal CACCC element in β globin gene promoter function is suggested by the observation that naturally occurring β thalassemia mutations affecting the proximal CACCC box are far more severe than those affecting the distal element. Nevertheless recent evidences demonstrate: that EKLF does indeed bind to the distal CACCC motif, although with low affinity. that the CCTCACCC is required for maximal stimulation of the β-globin gene by EKLF and that silent β-thalassemia due to mutations of the distal CACCC box affects the binding and responsiveness to EKLF of the β-globin gene promoter. Our interest in the function of the distal CACCC element springs from the observation that β thalassemia mutation affecting the distal box show an age related pattern of expression being more severe in the childhood than in the adulthood. In order to get light inside the role of this element in the function of the β globin gene and in the γ to β hemoglobin switching we have analyzed the effect of mutations at the proximal and distal element “in vivo”. We have engineered, by site specific mutagenesis, the β-101 (distal CACCC element) and β-87 (proximal CACCC element) mutations inside the “minilocus “ γ-β construct. The minilocus construct has been widely used to study hemoglobin switching in vivo. This construct contains the full β-globin Locus Control Region (LCR), the Aγ globin gene, the β-globin gene and the 3′ hypersensitive site (HS) of the β-globin cluster. Three mice transgenic lines have been produced. The pattern of g versus β-globin switching has been analyzed during the development by S1 analysis and real time PCR. We have dissected the yolk sac at 10 days post conception (pc) to asses the embryonic stage of erythopoiesis; the fetal liver at 12, 14 and 16 days pc to asses the fetal stage or erythropoiesis when the g to b competitive switching take place; and the adult blood. Our results indicated that neither the β-101 nor the β-87 thalassemia mutations affect the competitive silencing of the b-globin gene in the yolk sac. During the fetal liver stage of erythropoiesis, were both human g and b human transgenes are expressed, the pattern of γ-β hemoglobin switching is striking different for the two different constructs. The b-87 minilocus γ-β construct shows a delayed switching patter mainly due to the low activation of the mutated β globin gene. The impairment of the expression of the β-87 globin gene became more severe during the fetal development compared to the control line. On the other hand the β-101 minilocus γ-β construct shows a γ-β hemoglobin switching pattern which is anticipated respect to the control line. In addition the effect of the β-101 mutation became less severe during the fetal development. These results highlight a possible role of the distal CACCC element in hemoglobin switching and in particular in the early stage of β-globin activation.
Sickle cell disease (SCD) is caused by the homozygous beta-globin gene mutation that can lead to ... more Sickle cell disease (SCD) is caused by the homozygous beta-globin gene mutation that can lead to ischemic multi-organ damage and consequently reduce life expectancy. On the other hand, sickle cell trait (SCT), the heterozygous beta-globin gene mutation, is still considered a benign condition. Although the mechanisms are not well understood, clinical evidence has recently shown that specific pathological symptoms can also be recognized in SCT carriers. So far, there are still scant data regarding the morphological modifications referable to possible multi-organ damage in the SCT condition. Therefore, after genotypic and hematological characterization, by conventional light microscopy and transmission electron microscopy (TEM), we investigated the presence of tissue alterations in 13 heterozygous Townes mice, one of the best-known animal models that, up to now, was used only for the study of the homozygous condition. We found that endothelial alterations, as among which the thickening...
Sickle cell disease (SCD) is a widespread genetic disease associated with severe disability and m... more Sickle cell disease (SCD) is a widespread genetic disease associated with severe disability and multi‐organ damage, resulting in a reduced life expectancy. None of the existing clinical treatments provide a solution for all patients. Gene therapy and fetal haemoglobin (HbF) reactivation through genetic approaches have obtained promising, but early, results in patients. Furthermore, the search for active molecules to increase HbF is still ongoing. The delta‐globin gene produces the delta‐globin of haemoglobin A2 (HbA2). Although expressed at a low level, HbA2 is fully functional and could be a valid anti‐sickling agent in SCD. To evaluate the therapeutic potential of a strategy aimed to over‐express the delta‐globin gene in vivo, we crossed transgenic mice carrying a single copy of the delta‐globin gene, genetically modified to be expressed at a higher level (activated), with a humanised mouse model of SCD. The activated delta‐globin gene gives rise to a consistent production of HbA2, effectively improving the SCD phenotype. For the first time in vivo, these results demonstrate the therapeutic potential of delta‐globin, which could lead to novel approaches to the cure of SCD.
The CACCC box is duplicated in the β globin gene promoter of humans and other mammals. While the ... more The CACCC box is duplicated in the β globin gene promoter of humans and other mammals. While the function of the proximal element as a binding site for EKLF has already been well established, the role of the distal element remains unclear The distal CACCC box has been previously reported not to bind EKLF in vitro. A minor role of the distal CACCC element in β globin gene promoter function is suggested by the observation that naturally occurring β thalassemia mutations affecting the proximal CACCC box are far more severe than those affecting the distal element. Nevertheless recent evidences demonstrate: that EKLF does indeed bind to the distal CACCC motif, although with low affinity. that the CCTCACCC is required for maximal stimulation of the β-globin gene by EKLF and that silent β-thalassemia due to mutations of the distal CACCC box affects the binding and responsiveness to EKLF of the β-globin gene promoter. Our interest in the function of the distal CACCC element springs from the...
The δ globin gene is the second adult β-like globin gene in humans and codes for the δ globin cha... more The δ globin gene is the second adult β-like globin gene in humans and codes for the δ globin chain which forms together with the α globin chain Hemoglobin A2 (HbA2). HbA2 represents less than 3% of the total hemoglobin in normal individuals and it is typically increased in β thalassemia carriers. The δ globin gene is highly homologous to the β globin gene since it derives from a common ancestor. In our previous work we (as well as others) have demonstrated, in vitro, that the creation of the β globin proximal CACCC box consensus sequence, the binding site of the trascription factor EKLF, on the δ globin gene promoter is sufficient to enhance its expression to a considerable extent. Here we show that the δ globin gene promoter can be activated “ in vivo” in a transgenic mice model. We have produced transgenic mice lines with a DNA construct in which the wild type (wt) β globin gene promoter and either the wt or the proximal CACCC box containing δ globin gene promoter are linked in c...
The human β globin locus spans an 80-kb chromosomal region encompassing both the five expressed g... more The human β globin locus spans an 80-kb chromosomal region encompassing both the five expressed globin genes and the cis-acting elements that direct their stage-specific expression during ontogeny. Sequences proximal to the genes and in the locus control region, 60 kb upstream of the adult β globin gene, are required for developmental regulation. Transgenic studies have shown that altering the structural organization of the locus disrupts the normal pattern of globin gene regulation. Procedures for introducing yeast artificial chromosomes (YACs) containing large genetic loci now make it possible to define the sequences required for stage-restricted gene expression in constructs that preserve the integrity of the β globin locus. We demonstrate that independent YAC transgenic lines exhibit remarkably similar patterns of globin gene expression during development. The switch from γ to β globin predominant expression occurs between day 11.5 and 12.5 of gestation, with no more than twofol...
2152 Hypersensitive site 2 (HS2) of the locus control region (LCR) is required for the optimal re... more 2152 Hypersensitive site 2 (HS2) of the locus control region (LCR) is required for the optimal regulation of the beta globin gene cluster. Screening a λgt11 cord blood cDNA library with the tandem NFE2 repeat of HS2 as recognition site probe, we isolated 14 cDNA clones of HMGB2, a chromatin non histone protein. Binding to the HS2 region was confirmed in vivo by ChIP assay. Transactivation analysis in K562 cells showed mild repression of a luciferase reporter driven by HS2 and the γ-promoter. The DNA bending capacity and the increased expression of HMGB2 during erythroid differentiation are properties well suited to facilitate LCR looping toward the β-globin genes, the mechanism thought to mediate globin gene activation. Hence, HMGB2 binding to HS2 may be relevant for the regulation of the β-globin gene cluster. To assess the function of HMGB2 as a possible regulator of the globin genes we analyzed the hematological phenotype of the HMGB2 knock out mice during erythroid differentiati...
A key regulatory gene in definitive erythropoiesis is the transcription factor Krüppel-like facto... more A key regulatory gene in definitive erythropoiesis is the transcription factor Krüppel-like factor 1 (Klf1). Klf1 null mice die in utero by day 15.5 (E15.5) due to impaired definitive erythropoiesis and severe anemia. Definitive erythropoiesis takes place in erythroblastic islands in mammals. Erythroblastic islands are formed by a central macrophage (Central Macrophage of Erythroblastic Island, CMEI) surrounded by maturating erythroblasts. Interferon-β (IFN-β) is activated in the fetal liver's CMEI of Klf1 null mice. The inhibitory effect of IFN-β on erythropoiesis is known and, therefore, we speculated that IFN-β could have contributed to the impairment of definitive erythropoiesis in Klf1 knockout (KO) mice fetal liver. To validate this hypothesis, in this work we determined whether the inactivation of type I interferon receptor (Ifnar1) would ameliorate the phenotype of Klf1 KO mice by improving the lethal anemia. Our results show a prolonged survival of Klf1/Ifnar1 double KO...
ABSTRACT The δ‐globin gene produces the δ chain of Hb A2 which represents less than 3% of the hem... more ABSTRACT The δ‐globin gene produces the δ chain of Hb A2 which represents less than 3% of the hemoglobin (Hb) in normal individuals. The δ‐globin gene is also expressed in the human erythroleukemia cell line K562. The expression of the δ‐globin gene in this cell line is unexpected since K562 shows an embryonic‐fetal globin gene expression pattern with no expression of the adult β‐globin gene. δ‐Globin gene activation has been proposed as a potential therapeutic tool for the cure of δ‐thalassemia (thal). In order to shed some light on the δ‐globin gene activation in K562 the present study has: (1) determined the complete nucleotide sequence of the δ‐ and β‐globin genes; (2) assessed, by reverse transcription‐polymerase chain reaction (RT‐PCR), the relative δ‐ and β‐globin mRNA level; and (3) analyzed the exact level of the endogenous expression δ‐globin gene by S1 mapping. No sequence variations were identified in the δ‐ and β‐globin genes when compared to the normal sequences. δ‐Globin mRNA represent more than 95% of the total δ + β‐mRNA content. The level of expression of the δ‐globin gene is 12.3% (±1.2) compared to the endogenous α‐globin gene. These results indicate that the high expression of the δ‐globin gene in K562 is most likely due to the transacting environment. Therefore, the presence and/or absence of specific transacting factors are able to specifically activate the human δ‐globin gene. The level of expression of the δ‐globin gene in this cell line suggests that it could be of relevance to identify the transacting factor(s) responsible for this selective activation in order to better understand the molecular mechanisms undergoing gene activation.
ABSTRACT The δ‐globin gene produces the δ chain of Hb A2 which represents less than 3% of the hem... more ABSTRACT The δ‐globin gene produces the δ chain of Hb A2 which represents less than 3% of the hemoglobin (Hb) in normal individuals. The δ‐globin gene is also expressed in the human erythroleukemia cell line K562. The expression of the δ‐globin gene in this cell line is unexpected since K562 shows an embryonic‐fetal globin gene expression pattern with no expression of the adult β‐globin gene. δ‐Globin gene activation has been proposed as a potential therapeutic tool for the cure of δ‐thalassemia (thal). In order to shed some light on the δ‐globin gene activation in K562 the present study has: (1) determined the complete nucleotide sequence of the δ‐ and β‐globin genes; (2) assessed, by reverse transcription‐polymerase chain reaction (RT‐PCR), the relative δ‐ and β‐globin mRNA level; and (3) analyzed the exact level of the endogenous expression δ‐globin gene by S1 mapping. No sequence variations were identified in the δ‐ and β‐globin genes when compared to the normal sequences. δ‐Globin mRNA represent more than 95% of the total δ + β‐mRNA content. The level of expression of the δ‐globin gene is 12.3% (±1.2) compared to the endogenous α‐globin gene. These results indicate that the high expression of the δ‐globin gene in K562 is most likely due to the transacting environment. Therefore, the presence and/or absence of specific transacting factors are able to specifically activate the human δ‐globin gene. The level of expression of the δ‐globin gene in this cell line suggests that it could be of relevance to identify the transacting factor(s) responsible for this selective activation in order to better understand the molecular mechanisms undergoing gene activation.
The CACCC box is duplicated in the β globin gene promoter of humans and other mammals. While the ... more The CACCC box is duplicated in the β globin gene promoter of humans and other mammals. While the function of the proximal element as a binding site for EKLF has already been well established, the role of the distal element remains unclear The distal CACCC box has been previously reported not to bind EKLF in vitro. A minor role of the distal CACCC element in β globin gene promoter function is suggested by the observation that naturally occurring β thalassemia mutations affecting the proximal CACCC box are far more severe than those affecting the distal element. Nevertheless recent evidences demonstrate: that EKLF does indeed bind to the distal CACCC motif, although with low affinity. that the CCTCACCC is required for maximal stimulation of the β-globin gene by EKLF and that silent β-thalassemia due to mutations of the distal CACCC box affects the binding and responsiveness to EKLF of the β-globin gene promoter. Our interest in the function of the distal CACCC element springs from the observation that β thalassemia mutation affecting the distal box show an age related pattern of expression being more severe in the childhood than in the adulthood. In order to get light inside the role of this element in the function of the β globin gene and in the γ to β hemoglobin switching we have analyzed the effect of mutations at the proximal and distal element “in vivo”. We have engineered, by site specific mutagenesis, the β-101 (distal CACCC element) and β-87 (proximal CACCC element) mutations inside the “minilocus “ γ-β construct. The minilocus construct has been widely used to study hemoglobin switching in vivo. This construct contains the full β-globin Locus Control Region (LCR), the Aγ globin gene, the β-globin gene and the 3′ hypersensitive site (HS) of the β-globin cluster. Three mice transgenic lines have been produced. The pattern of g versus β-globin switching has been analyzed during the development by S1 analysis and real time PCR. We have dissected the yolk sac at 10 days post conception (pc) to asses the embryonic stage of erythopoiesis; the fetal liver at 12, 14 and 16 days pc to asses the fetal stage or erythropoiesis when the g to b competitive switching take place; and the adult blood. Our results indicated that neither the β-101 nor the β-87 thalassemia mutations affect the competitive silencing of the b-globin gene in the yolk sac. During the fetal liver stage of erythropoiesis, were both human g and b human transgenes are expressed, the pattern of γ-β hemoglobin switching is striking different for the two different constructs. The b-87 minilocus γ-β construct shows a delayed switching patter mainly due to the low activation of the mutated β globin gene. The impairment of the expression of the β-87 globin gene became more severe during the fetal development compared to the control line. On the other hand the β-101 minilocus γ-β construct shows a γ-β hemoglobin switching pattern which is anticipated respect to the control line. In addition the effect of the β-101 mutation became less severe during the fetal development. These results highlight a possible role of the distal CACCC element in hemoglobin switching and in particular in the early stage of β-globin activation.
Sickle cell disease (SCD) is caused by the homozygous beta-globin gene mutation that can lead to ... more Sickle cell disease (SCD) is caused by the homozygous beta-globin gene mutation that can lead to ischemic multi-organ damage and consequently reduce life expectancy. On the other hand, sickle cell trait (SCT), the heterozygous beta-globin gene mutation, is still considered a benign condition. Although the mechanisms are not well understood, clinical evidence has recently shown that specific pathological symptoms can also be recognized in SCT carriers. So far, there are still scant data regarding the morphological modifications referable to possible multi-organ damage in the SCT condition. Therefore, after genotypic and hematological characterization, by conventional light microscopy and transmission electron microscopy (TEM), we investigated the presence of tissue alterations in 13 heterozygous Townes mice, one of the best-known animal models that, up to now, was used only for the study of the homozygous condition. We found that endothelial alterations, as among which the thickening...
Sickle cell disease (SCD) is a widespread genetic disease associated with severe disability and m... more Sickle cell disease (SCD) is a widespread genetic disease associated with severe disability and multi‐organ damage, resulting in a reduced life expectancy. None of the existing clinical treatments provide a solution for all patients. Gene therapy and fetal haemoglobin (HbF) reactivation through genetic approaches have obtained promising, but early, results in patients. Furthermore, the search for active molecules to increase HbF is still ongoing. The delta‐globin gene produces the delta‐globin of haemoglobin A2 (HbA2). Although expressed at a low level, HbA2 is fully functional and could be a valid anti‐sickling agent in SCD. To evaluate the therapeutic potential of a strategy aimed to over‐express the delta‐globin gene in vivo, we crossed transgenic mice carrying a single copy of the delta‐globin gene, genetically modified to be expressed at a higher level (activated), with a humanised mouse model of SCD. The activated delta‐globin gene gives rise to a consistent production of HbA2, effectively improving the SCD phenotype. For the first time in vivo, these results demonstrate the therapeutic potential of delta‐globin, which could lead to novel approaches to the cure of SCD.
The CACCC box is duplicated in the β globin gene promoter of humans and other mammals. While the ... more The CACCC box is duplicated in the β globin gene promoter of humans and other mammals. While the function of the proximal element as a binding site for EKLF has already been well established, the role of the distal element remains unclear The distal CACCC box has been previously reported not to bind EKLF in vitro. A minor role of the distal CACCC element in β globin gene promoter function is suggested by the observation that naturally occurring β thalassemia mutations affecting the proximal CACCC box are far more severe than those affecting the distal element. Nevertheless recent evidences demonstrate: that EKLF does indeed bind to the distal CACCC motif, although with low affinity. that the CCTCACCC is required for maximal stimulation of the β-globin gene by EKLF and that silent β-thalassemia due to mutations of the distal CACCC box affects the binding and responsiveness to EKLF of the β-globin gene promoter. Our interest in the function of the distal CACCC element springs from the...
The δ globin gene is the second adult β-like globin gene in humans and codes for the δ globin cha... more The δ globin gene is the second adult β-like globin gene in humans and codes for the δ globin chain which forms together with the α globin chain Hemoglobin A2 (HbA2). HbA2 represents less than 3% of the total hemoglobin in normal individuals and it is typically increased in β thalassemia carriers. The δ globin gene is highly homologous to the β globin gene since it derives from a common ancestor. In our previous work we (as well as others) have demonstrated, in vitro, that the creation of the β globin proximal CACCC box consensus sequence, the binding site of the trascription factor EKLF, on the δ globin gene promoter is sufficient to enhance its expression to a considerable extent. Here we show that the δ globin gene promoter can be activated “ in vivo” in a transgenic mice model. We have produced transgenic mice lines with a DNA construct in which the wild type (wt) β globin gene promoter and either the wt or the proximal CACCC box containing δ globin gene promoter are linked in c...
The human β globin locus spans an 80-kb chromosomal region encompassing both the five expressed g... more The human β globin locus spans an 80-kb chromosomal region encompassing both the five expressed globin genes and the cis-acting elements that direct their stage-specific expression during ontogeny. Sequences proximal to the genes and in the locus control region, 60 kb upstream of the adult β globin gene, are required for developmental regulation. Transgenic studies have shown that altering the structural organization of the locus disrupts the normal pattern of globin gene regulation. Procedures for introducing yeast artificial chromosomes (YACs) containing large genetic loci now make it possible to define the sequences required for stage-restricted gene expression in constructs that preserve the integrity of the β globin locus. We demonstrate that independent YAC transgenic lines exhibit remarkably similar patterns of globin gene expression during development. The switch from γ to β globin predominant expression occurs between day 11.5 and 12.5 of gestation, with no more than twofol...
2152 Hypersensitive site 2 (HS2) of the locus control region (LCR) is required for the optimal re... more 2152 Hypersensitive site 2 (HS2) of the locus control region (LCR) is required for the optimal regulation of the beta globin gene cluster. Screening a λgt11 cord blood cDNA library with the tandem NFE2 repeat of HS2 as recognition site probe, we isolated 14 cDNA clones of HMGB2, a chromatin non histone protein. Binding to the HS2 region was confirmed in vivo by ChIP assay. Transactivation analysis in K562 cells showed mild repression of a luciferase reporter driven by HS2 and the γ-promoter. The DNA bending capacity and the increased expression of HMGB2 during erythroid differentiation are properties well suited to facilitate LCR looping toward the β-globin genes, the mechanism thought to mediate globin gene activation. Hence, HMGB2 binding to HS2 may be relevant for the regulation of the β-globin gene cluster. To assess the function of HMGB2 as a possible regulator of the globin genes we analyzed the hematological phenotype of the HMGB2 knock out mice during erythroid differentiati...
A key regulatory gene in definitive erythropoiesis is the transcription factor Krüppel-like facto... more A key regulatory gene in definitive erythropoiesis is the transcription factor Krüppel-like factor 1 (Klf1). Klf1 null mice die in utero by day 15.5 (E15.5) due to impaired definitive erythropoiesis and severe anemia. Definitive erythropoiesis takes place in erythroblastic islands in mammals. Erythroblastic islands are formed by a central macrophage (Central Macrophage of Erythroblastic Island, CMEI) surrounded by maturating erythroblasts. Interferon-β (IFN-β) is activated in the fetal liver's CMEI of Klf1 null mice. The inhibitory effect of IFN-β on erythropoiesis is known and, therefore, we speculated that IFN-β could have contributed to the impairment of definitive erythropoiesis in Klf1 knockout (KO) mice fetal liver. To validate this hypothesis, in this work we determined whether the inactivation of type I interferon receptor (Ifnar1) would ameliorate the phenotype of Klf1 KO mice by improving the lethal anemia. Our results show a prolonged survival of Klf1/Ifnar1 double KO...
ABSTRACT The δ‐globin gene produces the δ chain of Hb A2 which represents less than 3% of the hem... more ABSTRACT The δ‐globin gene produces the δ chain of Hb A2 which represents less than 3% of the hemoglobin (Hb) in normal individuals. The δ‐globin gene is also expressed in the human erythroleukemia cell line K562. The expression of the δ‐globin gene in this cell line is unexpected since K562 shows an embryonic‐fetal globin gene expression pattern with no expression of the adult β‐globin gene. δ‐Globin gene activation has been proposed as a potential therapeutic tool for the cure of δ‐thalassemia (thal). In order to shed some light on the δ‐globin gene activation in K562 the present study has: (1) determined the complete nucleotide sequence of the δ‐ and β‐globin genes; (2) assessed, by reverse transcription‐polymerase chain reaction (RT‐PCR), the relative δ‐ and β‐globin mRNA level; and (3) analyzed the exact level of the endogenous expression δ‐globin gene by S1 mapping. No sequence variations were identified in the δ‐ and β‐globin genes when compared to the normal sequences. δ‐Globin mRNA represent more than 95% of the total δ + β‐mRNA content. The level of expression of the δ‐globin gene is 12.3% (±1.2) compared to the endogenous α‐globin gene. These results indicate that the high expression of the δ‐globin gene in K562 is most likely due to the transacting environment. Therefore, the presence and/or absence of specific transacting factors are able to specifically activate the human δ‐globin gene. The level of expression of the δ‐globin gene in this cell line suggests that it could be of relevance to identify the transacting factor(s) responsible for this selective activation in order to better understand the molecular mechanisms undergoing gene activation.
ABSTRACT The δ‐globin gene produces the δ chain of Hb A2 which represents less than 3% of the hem... more ABSTRACT The δ‐globin gene produces the δ chain of Hb A2 which represents less than 3% of the hemoglobin (Hb) in normal individuals. The δ‐globin gene is also expressed in the human erythroleukemia cell line K562. The expression of the δ‐globin gene in this cell line is unexpected since K562 shows an embryonic‐fetal globin gene expression pattern with no expression of the adult β‐globin gene. δ‐Globin gene activation has been proposed as a potential therapeutic tool for the cure of δ‐thalassemia (thal). In order to shed some light on the δ‐globin gene activation in K562 the present study has: (1) determined the complete nucleotide sequence of the δ‐ and β‐globin genes; (2) assessed, by reverse transcription‐polymerase chain reaction (RT‐PCR), the relative δ‐ and β‐globin mRNA level; and (3) analyzed the exact level of the endogenous expression δ‐globin gene by S1 mapping. No sequence variations were identified in the δ‐ and β‐globin genes when compared to the normal sequences. δ‐Globin mRNA represent more than 95% of the total δ + β‐mRNA content. The level of expression of the δ‐globin gene is 12.3% (±1.2) compared to the endogenous α‐globin gene. These results indicate that the high expression of the δ‐globin gene in K562 is most likely due to the transacting environment. Therefore, the presence and/or absence of specific transacting factors are able to specifically activate the human δ‐globin gene. The level of expression of the δ‐globin gene in this cell line suggests that it could be of relevance to identify the transacting factor(s) responsible for this selective activation in order to better understand the molecular mechanisms undergoing gene activation.
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Papers by Susanna Porcu