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• W2090147011 abstract "MicroRNAs (miRNAs) are small, 22- to 25-nt-long, endogenous, non-protein-coding RNA molecules which have the potential to downregulate gene expression. The involvement of miRNAs in several biological processes has been demonstrated, and diseased states are characterized by altered expression of miRNAs [1]. We intended to study how the miRNA expression profile is modulated in patients with β thalassemia major.Thalassemia is characterized by an enhanced rate of growth of erythropoietic progenitors leading to marrow expansion and resultant iron absorption [2]. Of the various miRNAs expressed during erythropoiesis, hsa-miR-503 has been implicated in regulation of genes involved in cell cycle arrest and apoptosis [3,4,5].To investigate whether there is a variance in the expression level of hsa-miR-503 in red blood cells of thalassemic and hematologically normal individuals, four patients with β thalassemia major, four with E-β thalassemia major, and two with E-β thalassemia intermedia, as well as four normal healthy adult volunteers, were recruited. All β major patients studied here are homozygous for the mutation IVS-I nt 5(G>C). The intermedia and severe patients of HbE/β thalassemia are compound heterozygous for HbE and IVS-I nt 5(G>C). All probands were aged between 20 and 30 years. Written informed consent was obtained from them, and the institutional human research committee approved the study. The ethical principles followed by the institute are guided by rules as formulated by the Indian Council of Medical Research and these are in agreement with the Helsinki rules.The CD34+ hematopoietic stem cells were first isolated from peripheral blood samples of these probands via the MACS cell separation technique and they were then grown following a two-step culture system to achieve the unilineage differentiation into mature erythrocytes [6]. Ninety percent of the cells became benzidine positive by day 13 in normal samples.The cells were harvested on the 13th day of culture by selecting for CD235a expression using an immunomagnetic isolation procedure and processed for miRNA and mRNA isolation (mir VanaTM miRNA Isolation Kit; Ambion). Solution hybridization was performed with an mir Vana miRNA Probe Construction Kit (Ambion) and an mir Vana miRNA Detection Kit (Ambion) following the manufacturer’s instructions. For probe labeling, α-32P CTP (BRIT, India) was used. The intensity of the bands was analyzed using Imagequant software. U6 SnRNA was used as an internal control in every sample.Figure 1a shows the box plot for the expression of hsa-miR 503 in normal and different thalassemia samples. The box plots and statistical analysis (two-tailed t test) were performed using Statistica 7 software. The expression was significantly lower than normal in β thalassemia major (p = 0.000029), E-β thalassemia major (p = 0.002678), or E-β thalassemia intermedia (p = 0.012369), with the level of significance increasing with increasing severity.As per Tarbase 6.0, there are thirteen validated target genes of hsa-miR-503. Among these thirteen, CDC25A, CCNE1, CCNF, and CHEK1 are expressed appreciably in erythrocytes (Gene Expression Atlas, www.ebi.ac.uk/gxa/).We followed the expression of CDC25A, one of the verified targets of has-miR-503, in cultured CD34+ cells on the 13th day of culture by real-time PCR. cDNA, synthesized using a Taqman® Reverse Transcription Reagents Kit (Applied Biosystems), was analyzed by quantitative PCR (qPCR) using a SYBR® Green PCR Core Reagents Kit (Applied Biosystems). Expression of CDC25A was found to be upregulated by ∼1,000 times in thalassemic individuals (normalized against GAPDH) (fig. 1b).The enhanced rate of growth of erythropoietic progenitors of thalassemic individuals remains unchanged in CD34+ progenitor cells cultured in vitro (fig. 1c). Our results corroborate other results where thalassemic progenitors multiply more, but are slower in differentiation milestones, compared to their normal counterparts [7]. In our system the progenitor cells of normal donors multiplied ∼100 times, but in thalassemic individuals the increase is much greater.It has been shown that during muscle cell differentiation hsa-miR-503 targets CDC25A, a phosphatase, which activates cyclin dependent kinase CDK1, responsible for controlling the transition from the G1 phase to the S phase and from G2 to the M phase [8]. It might be construed that, in a similar manner, during normal erythropoiesis, miR-503 along with other factors promotes differentiation and silences the genes associated with cell proliferation, leading to cell cycle quiescence. During erythropoiesis in the thalassemia patients, it fails to be expressed, leading to continued expression of CDC25A and excessive growth and ineffective eythropoiesis characteristic of the disease.Thus, our experiments suggest that failure to induce hsa-miR-503 might have a role in the accelerated growth of erythropoietic cells of thalassemic adults and needs to be investigated further.Financial assistance from the Department of Biotechnology (BT/PR9036/BRB/10/537/2007) and the University Grants Commission (UGC/194/UPE/ 2007/2) is acknowledged. P.R. is an Indian Council of Medical Research Senior Research Fellow (45/2/2010-Hae/BMS)." @default.
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• W2090147011 date "2012-01-01" @default.
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• W2090147011 title "hsa-miR-503 Is Downregulated in β Thalassemia Major" @default.
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• W2090147011 doi "https://doi.org/10.1159/000339492" @default.
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