Multiple physical stresses induce γ-globin gene expression and fetal hemoglobin production in erythroid cells

Schaeffer, Emily K.; West, Rachel J.; Conine, Sarah; Lowrey, Christopher H.

doi:10.1016/j.bcmd.2013.10.007

Cited by 15 publications

(8 citation statements)

References 50 publications

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“…However, the RBCs of several PKAN patients and their family members contained increased HbF levels ( Fig 5A ). These findings may indicate alterations in erythropoiesis in patients with PKAN [ 20 ].…”

Section: Resultsmentioning

confidence: 99%

Abnormal Red Cell Structure and Function in Neuroacanthocytosis

et al. 2015

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BackgroundPanthothenate kinase-associated neurodegeneration (PKAN) belongs to a group of hereditary neurodegenerative disorders known as neuroacanthocytosis (NA). This genetically heterogeneous group of diseases is characterized by degeneration of neurons in the basal ganglia and by the presence of deformed red blood cells with thorny protrusions, acanthocytes, in the circulation.ObjectiveThe goal of our study is to elucidate the molecular mechanisms underlying this aberrant red cell morphology and the corresponding functional consequences. This could shed light on the etiology of the neurodegeneration.MethodsWe performed a qualitative and semi-quantitative morphological, immunofluorescent, biochemical and functional analysis of the red cells of several patients with PKAN and, for the first time, of the red cells of their family members.ResultsWe show that the blood of patients with PKAN contains not only variable numbers of acanthocytes, but also a wide range of other misshapen red cells. Immunofluorescent and immunoblot analyses suggest an altered membrane organization, rather than quantitative changes in protein expression. Strikingly, these changes are not limited to the red blood cells of PKAN patients, but are also present in the red cells of heterozygous carriers without neurological problems. Furthermore, changes are not only present in acanthocytes, but also in other red cells, including discocytes. The patients’ cells, however, are more fragile, as observed in a spleen-mimicking device.ConclusionThese morphological, molecular and functional characteristics of red cells in patients with PKAN and their family members offer new tools for diagnosis and present a window into the pathophysiology of neuroacanthocytosis.

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Section: Resultsmentioning

confidence: 99%

Abnormal Red Cell Structure and Function in Neuroacanthocytosis

et al. 2015

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“…For example, SIRT1 deacetylates and increases the transcription function of FOXO3a, which has been shown to regulate HBG transcription . SIRT1 was also involved in the stress response that upregulates HBG expression . In addition, more extensive studies in vitro and in vivo are needed to completely understand the role of SIRT1 in cell differentiation.…”

Section: Discussionmentioning

confidence: 99%

SIRT1 activates the expression of fetal hemoglobin genes

et al. 2017

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High fetal hemoglobin (HbF, α2γ2) levels ameliorate the clinical manifestations of sickle cell disease and β thalassemia. The mechanisms that repress HbF expression and silence γ-globin genes in adults are incompletely characterized and only a single HbF inducer, hydroxyurea, is approved for treatment, and only in patients with sickle cell disease. We identified SIRT1, a protein deacetylase, as a new inducer of γ-globin. SIRT1 knockdown decreased, while SIRT1 ectopic expression upregulated γ-globin gene (HBG) expression in primary human erythroid cells and in K562 cells. The small molecule SIRT1 activators SRT2104 and SRT1720 enhanced HBG expression in cord blood human erythroblasts and reactivated silenced HBG in adult human erythroblasts. Furthermore, SIRT1 binds in the β-globin gene cluster locus control region (LCR) and HBG promoters, promotes the looping of the LCR to HBG promoter, and increases the binding of RNA polymerase II and H4K16Ac in the HBG promoter. SIRT1 suppressed the expression of the HBG suppressors BCL11A, KLF1, HDAC1 and HDAC2. Lastly, SIRT1 did not change the proliferation of human erythroid progenitor cells or the expression of differentiation marker CD235a. These data suggest that SIRT1 activates HBG expression through facilitating LCR looping to the HBG promoter, inhibiting the expression of transcriptional suppressors of HBG, and indirectly increasing histone acetylation in the HBG promoter. SIRT1 is a potential therapeutic target for γ-globin gene induction, and small molecule SIRT1 activators might serve as a lead compound for the development of new HbF inducers.

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“…Many compounds have been found to stimulate γ-globin gene expression, in preclinical systems, acting through a variety of cellular and molecular mechanisms[ 4 – 6 , 11 – 13 , 17 , 18 , 37 , 38 ]. The cytotoxic agents, were initially thought to accelerate the maturation of erythroid precursors and produce progeny which maintained the “fetal stage” of globin switching.…”

Section: Discussionmentioning

confidence: 99%

“…The cytotoxic agents, were initially thought to accelerate the maturation of erythroid precursors and produce progeny which maintained the “fetal stage” of globin switching. Other investigators have generated evidence that these drugs may produce a cellular stress response or other signaling pathways that contribute to fetal globin expression[ 34 – 37 ]. Agents which act “directly” on the γ-globin promoter include a variety of compounds of which some disrupt repressor complexes regulating γ-globin gene expression[ 3 – 6 , 11 – 13 , 17 ].…”

Section: Discussionmentioning

confidence: 99%

Novel Inducers of Fetal Globin Identified through High Throughput Screening (HTS) Are Active In Vivo in Anemic Baboons and Transgenic Mice

et al. 2015

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High-level fetal (γ) globin expression ameliorates clinical severity of the beta (β) hemoglobinopathies, and safe, orally-bioavailable γ-globin inducing agents would benefit many patients. We adapted a LCR-γ-globin promoter-GFP reporter assay to a high-throughput robotic system to evaluate five diverse chemical libraries for this activity. Multiple structurally- and functionally-diverse compounds were identified which activate the γ-globin gene promoter at nanomolar concentrations, including some therapeutics approved for other conditions. Three candidates with established safety profiles were further evaluated in erythroid progenitors, anemic baboons and transgenic mice, with significant induction of γ-globin expression observed in vivo. A lead candidate, Benserazide, emerged which demonstrated > 20-fold induction of γ-globin mRNA expression in anemic baboons and increased F-cell proportions by 3.5-fold in transgenic mice. Benserazide has been used chronically to inhibit amino acid decarboxylase to enhance plasma levels of L-dopa. These studies confirm the utility of high-throughput screening and identify previously unrecognized fetal globin inducing candidates which can be developed expediently for treatment of hemoglobinopathies.

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Multiple physical stresses induce γ-globin gene expression and fetal hemoglobin production in erythroid cells

Cited by 15 publications

References 50 publications

Abnormal Red Cell Structure and Function in Neuroacanthocytosis

Abnormal Red Cell Structure and Function in Neuroacanthocytosis

SIRT1 activates the expression of fetal hemoglobin genes

Novel Inducers of Fetal Globin Identified through High Throughput Screening (HTS) Are Active In Vivo in Anemic Baboons and Transgenic Mice

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