Impact of epigenetic mechanisms on therapeutic approaches of hemoglobinopathies

Costa, Dário Alves da Silva; Capuano, M.; Sommese, Linda; Napoli, Claudio

doi:10.1016/j.bcmd.2015.05.004

Cited by 15 publications

(8 citation statements)

References 68 publications

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“…Another limitation of the present work the “promiscuous” nature of HU, as it could influence many aspects of cellular functions and almost certainly alter the global cellular transcriptome. Therefore, future studies should continue to evaluate the in vivo impact of efficacious concentrations of HU on the erythroblast transcriptome and/or proteome, as well as the erythroid-specific micronome of SCD patients (before treatment and at MTD) as global analysis of these epigenetic mechanisms could highlight multiple components of this complex system and possibly yield alternative (possibly miRNA-based) therapeutic approaches to hemoglobinopathies [ 78 ]. This is likely not implausible as several clinical trials in other diseases have demonstrated a promising future for miRNA-based therapeutics such as the liposome-based human miR-34 mimic (MRX-34) miRNA-based drug against hepatocellular carcinoma (NCT01829971).…”

Section: Discussionmentioning

confidence: 99%

Hydroxyurea down‐regulates BCL11A, KLF‐1 and MYB through miRNA‐mediated actions to induce γ‐globin expression: implications for new therapeutic approaches of sickle cell disease

Pule

Mowla

Novitzky

et al. 2016

Clinical & Translational Med

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Background The major therapeutic benefit of hydroxyurea, the only FDA-approved pharmacologic treatment for sickle cell disease (SCD), is directly related to fetal hemoglobin (HbF) production that leads to significant reduction of morbidity and mortality. However, potential adverse effects such as infertility, susceptibility to infections, or teratogenic effect have been subject of concerns. Therefore, understanding HU molecular mechanisms of action, could lead to alternative therapeutic agents to increase HbF with less toxicity. This paper investigated whether HU-induced HbF could operate through post-transcriptional miRNAs regulation of BCL11A, KLF - 1 and MYB, potent negative regulators of HbF. Both ex vivo differentiated primary erythroid cells from seven unrelated individuals, and K562 cells were treated with hydroxyurea (100 μM) and changes in BCL11A , KLF - 1 , GATA - 1 , MYB, β- and γ-globin gene expression were investigated. To explore potential mechanisms of post-transcriptional regulation, changes in expression of seven targeted miRNAs, previously associated with basal γ-globin expression were examined using miScript primer assays. In addition, K562 cells were transfected with miScript miRNA inhibitors/anti-miRNAs followed by Western Blot analysis to assess the effect on HbF protein levels. Direct interaction between miRNAs and the MYB 3′-untranslated region (UTR) was also investigated by a dual-luciferase reporter assays. Results Down-regulation of BCL11A and MYB was associated with a sevenfold increase in γ-globin expression in both primary and K562 cells (p < 0.003). Similarly, KLF - 1 was down-regulated in both cell models, corresponding to the repressed expression of BCL11A and β-globin gene (p < 0.04). HU induced differential expression of all miRNAs in both cell models, particularly miR-15a, miR-16, miR-26b and miR-151-3p. An HU-induced miRNAs-mediated mechanism of HbF regulation was illustrated with the inhibition of miR-26b and -151-3p resulting in reduced HbF protein levels. There was direct interaction between miR-26b with the MYB 3′-untranslated region (UTR). Conclusions These experiments have shown the association between critical regulators of γ-globin expression ( MYB , BCL11A and KLF - 1 ) and specific miRNAs; in response to HU, and demonstrated a mechanism of HbF production through HU-induced miRNAs inhibition of MYB . The role of miRNAs-mediated post-tra...

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Section: Discussionmentioning

confidence: 99%

Hydroxyurea down‐regulates BCL11A, KLF‐1 and MYB through miRNA‐mediated actions to induce γ‐globin expression: implications for new therapeutic approaches of sickle cell disease

Pule

Mowla

Novitzky

et al. 2016

Clinical & Translational Med

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“…Although the mechanism through which HU induces HbF reactivation is still not completely understood, HU treatment was found to increase HbF levels and reduce HbS polymerization, thus improving clinical symptoms and quality of life of these patients. Another epigenetic approach was also exploited through the use of HDAC inhibitors, including butyrate and its derivatives that have been demonstrated to stimulate HbF production in β-thalassemia patients [49].…”

Section: Novel Therapeutic Approaches For β-Thalassemiamentioning

confidence: 99%

Transcriptional Repressors of Fetal Globin Genes as Novel Therapeutic Targets in Beta-Thalassemia

Martino¹,

Sessa²,

Storino³

et al. 2020

Beta Thalassemia

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During development the human β-globin gene cluster undergoes two switching processes at the embryo-fetal and fetal-adult stages, respectively, involving changes in chromatin remodeling and in transcriptional regulatory networks. In particular, during the perinatal period, the switch from fetal-to-adult globin gene expression leads to fetal globin genes silencing and progressive decline of fetal hemoglobin (HbF). Impaired hemoglobin switching is associated with hereditary persistence of HbF (HPFH), a condition in which the fetal globin genes fail to be completely silenced in adult red blood cells. This condition, when co-inherited with hemoglobinopathies, has great therapeutic potential because elevated HbF levels can ameliorate β-thalassemia and sickle cell anemia. Therefore, there is a growing interest about the complex network of factors that regulate fetal globin genes expression. Here we discuss the activity of transcriptional repressors of fetal globin genes and their potential role as novel therapeutic targets in β-thalassemia.

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“…Moreover, butyrate regulates gene expression through inhibition of HDACs [Chuang et al, ; Thomas, ; Forsythe et al, ; Grayson et al, ; Ralph et al, ; Blouin et al, ; Canani et al, ; De Vadder et al, ], increases levels of mitochondrial apoptotic priming [Sarosiek et al, ] via, for example, the proapoptotic effector BCL2‐associated X (BAX) protein [Dmitriev and Papkovsky, ; Salama et al, ; Vahid et al, ], inhibits nuclear factor kappa‐B activation [Galland, ], and induces expression of Nrf2, leading to its accumulation [Endo et al, ; Vahid et al, ]. Butyrate has validated therapeutic utility in epigenetic treatments of a wide range of conditions ranging from the hematologic diseases, thalassemia and sickle cell anemia [Pace et al, ; Perrine, ; Mai, ; Perrine et al ; Costa et al, ], to neurodegenerative disorders like spinocerebellar ataxia type 3 [Chou et al, ], Alzheimer [Sezgin and Dincer, ], and Parkinson [Harrison and Dexter, ] diseases. Butyrate enhances the formation and recovery of memory in rodents [Guan et al, ; Aoyama et al, ; Blank et al, ], and stimulates neurogenesis in brain ischemia [Kim et al, ; Ariff et al, ; Swaminathan et al, ].…”

Section: Epigenetic Pathways and Butyratementioning

confidence: 99%

Epigenetic Treatment of Neuropsychiatric Disorders: Autism and Schizophrenia

Moos

Maneta

Pinkert

et al. 2016

Drug Development Research

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Neuropsychiatric disorders are a heterogeneous group of conditions that often share underlying mitochondrial dysfunction and biological pathways implicated in their pathogenesis, progression, and treatment. To date, these disorders have proven notoriously resistant to molecular-targeted therapies, and clinical options are relegated to interventional types, which do not address the core symptoms of the disease. In this review, we discuss emerging epigenetic-driven approaches using novel acylcarnitine esters (carnitinoids) that act on master regulators of antioxidant and cytoprotective genes and mitophagic pathways. These carnitinoids are actively transported, mitochondria-localizing, biomimetic coenzyme A surrogates of short-chain fatty acids, which inhibit histone deacetylase and may reinvigorate synaptic plasticity and protect against neuronal damage. We outline these neuroprotective effects in the context of treatment of neuropsychiatric disorders such as autism spectrum disorder and schizophrenia.

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Impact of epigenetic mechanisms on therapeutic approaches of hemoglobinopathies

Cited by 15 publications

References 68 publications

Hydroxyurea down‐regulates BCL11A, KLF‐1 and MYB through miRNA‐mediated actions to induce γ‐globin expression: implications for new therapeutic approaches of sickle cell disease

Hydroxyurea down‐regulates BCL11A, KLF‐1 and MYB through miRNA‐mediated actions to induce γ‐globin expression: implications for new therapeutic approaches of sickle cell disease

Transcriptional Repressors of Fetal Globin Genes as Novel Therapeutic Targets in Beta-Thalassemia

Epigenetic Treatment of Neuropsychiatric Disorders: Autism and Schizophrenia

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