In vivo Modulation of Human β-globin Gene Switching

Tanimoto, Koichi; Engel, James Douglas

doi:10.1016/s1050-1738(00)00035-9

Cited by 4 publications

(4 citation statements)

References 35 publications

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“…Fetal haemoglobin expression is a quantitative trait involving complex interactions among chromosome remodelling activities, transcription factors, genes modulating erythropoiesis and elements linked to the β ‐globin gene cluster, providing ample opportunity for genetic modulation (Tuan et al , 1985; Forrester et al , 1987; Grosveld et al , 1993; Weiss & Orkin, 1995; Tanimoto & Engel, 2000; Blobel & Weiss, 2001).…”

Section: Genetic Regulation Of Hbfmentioning

confidence: 99%

Predicting clinical severity in sickle cell anaemia

2005

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Summary The ability to predict the phenotype of an individual with sickle cell anaemia would allow a reliable prognosis and could guide therapeutic decision making. Some risk factors for individual disease complications are known but are insufficiently precise to use for prognostic purposes; predicting the global disease severity is not yet possible. Genetic association studies, which attempt to link gene polymorphisms with selected disease subphenotypes, may eventually provide useful methods of foretelling the likelihood of certain complications and allow better individualized treatment.

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Section: Genetic Regulation Of Hbfmentioning

confidence: 99%

Predicting clinical severity in sickle cell anaemia

2005

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“…[10][11][12][13] The regulation of HbF level might be a complex genetic trait governed by genetic elements linked to the b-globin gene-like cluster and quantitative trait loci (QTL) present on chromosomes 6, 8 and on the X-chromosome; other regulatory loci are also likely to exist and epigenetic and cellular factors could also have regulatory roles. [14][15][16][17][18][19][20][21][22][23][24][25][26][27] It is possible that these and other regulatory elements also modulate the HbF response to HU. Accordingly, we hypothesized that single nucleotide polymorphisms (SNPs) in candidate genes or QTL with putative roles in the regulation of HbF production might modulate the HbF response to treatment with HU.…”

Section: Introductionmentioning

confidence: 99%

Fetal hemoglobin in sickle cell anemia: genetic determinants of response to hydroxyurea

et al. 2007

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The increase in fetal hemoglobin (HbF) in response to hydroxyurea (HU) varies among patients with sickle cell anemia. Twenty-nine candidate genes within loci previously reported to be linked to HbF level (6q22.3-q23.2, 8q11-q12 and Xp22.2-p22.3), involved in metabolism of HU and related to erythroid progenitor proliferation were studied in 137 sickle cell anemia patients treated with HU. Three-hundred and twenty tagging single nucleotide polymorphisms (SNPs) for genotyping were selected based on HapMap data. Multiple linear regression and the nonlinear regression Random Forest method were used to investigate the association between SNPs and the change in HbF level after 2 years of treatment with HU. Both methods revealed that SNPs in genes within the 6q22.3-23.2 and 8q11-q12 linkage peaks, and also the ARG2, FLT1, HAO2 and NOS1 genes were associated with the HbF response to HU. Polymorphisms in genes regulating HbF expression, HU metabolism and erythroid progenitor proliferation might modulate the patient response to HU.

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“…The regulatory regions of many erythroid genes [e.g., the locuscontrol region (LCRs) of the β and α globin gene families (6,(15)(16)(17)] consist of the Maf recognition element (MARE) that can be bound with a diverse set of leucine-zipper factors including p45, Bach1, Nrf1, and Nrf2, all of which could associate with the small Maf subunit as heterodimers (18)(19)(20). In undifferentiated MEL, the Bach1/sMaf heterodimer interacts with the MARE and thus, inhibits the expression of both erythroid-specific genes, including the globins and ubiquitous genes like the heme oxygenase 1.…”

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confidence: 99%

JNK-mediated turnover and stabilization of the transcription factor p45/NF-E2 during differentiation of murine erythroleukemia cells

Lee

Shyu

Hsu

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Regulation of the homeostatic concentrations of specific sets of transcription factors is essential for correct programming of cell proliferation and differentiation. We have characterized the signal transduction pathways regulating the catabolisis of p45/NF-E2, a bZIP factor activating the erythroid and megakaryocytic gene transcription. Through use of different approaches including nano-scale proteomics, we show that activated-JNK, or Phospho-JNK (P-JNK), physically interacts with p45/NF-E2 and phosphorylates its Ser157 residue. This reaction leads to the poly-ubiquitination of p45/NF-E2 at one or more of six Lys residues, one of which being also a sumoylation site, and its degradation through the proteasome pathway. Significantly, this regulatory pathway of p45/NF-E2 by P-JNK exists only in uninduced murine erythroleukemia (MEL) cells but not in differentiated MEL cells in which JNK is inactivated on DMSO induction. Based on the above data and analysis of the chromatin-binding kinetics of p45/NF-E2 and the erythroid gene repressor Bach1 during the early phase of MEL differentiation, we suggest a model for the regulation of erythroid maturation. In the model, the posttranslational modifications and turnover of p45/NF-E2, as mediated by P-JNK, contribute to the control of its homeostatic concentration and consequently, its regulatory functions in the progression of erythroid differentiation and erythroid gene expression.egulation of erythroid differentiation is complex and occurs in multiple steps. Cytokines and nuclear hormones all play important roles in the maturation of erythroid cells. For example, it is known that signaling from the erythropoietin (Epo) receptor activates several pathways to promote cell proliferation, differentiation, and survival (1). Transcription factors such as GATA-1, EKLF, Bach1, and NF-E2 are also crucial for regulation of erythroid differentiation and maturation (2, 3). Among the many systems for studying the molecular mechanisms of erythroid differentiation is MEL (4-6). The MEL cells are derived from murine erythroleukemia by infection of the Friend virus, causing Epo-independent polyclonal expansion through a constitutive activation of the Epo receptor (7). During the early hours after exposure to differentiation-inducing agents such as DMSO or hexamethylene bisacetamide (HMBA), MEL cells undergo alterations that commit them to cessation of growth and to development of the characteristics of differentiation (8, 9).Multiple kinases are involved during MEL differentiation. For example, the inhibition of PI3 kinase reduces the GATA-1 binding to its DNA targets and thus, prevents MEL differentiation. On one hand, the PKC δ, and possibly PKC ε and PKC ζ as well, also plays a role in the HMBA-mediated differentiation of MEL, although their downstream targets are not clear yet (10). On the other hand, the MAPK families including p38, JNK, and ERK have been shown to be essential for Epo-dependent cell growth (11,12). This subfamily of the MAPK, including JNK and p38, could be activate...

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In vivo Modulation of Human β-globin Gene Switching

Cited by 4 publications

References 35 publications

Predicting clinical severity in sickle cell anaemia

Predicting clinical severity in sickle cell anaemia

Fetal hemoglobin in sickle cell anemia: genetic determinants of response to hydroxyurea

JNK-mediated turnover and stabilization of the transcription factor p45/NF-E2 during differentiation of murine erythroleukemia cells

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