MicroRNA-486-3p regulates γ-globin expression in human erythroid cells by directly modulating BCL11A.
MicroRNA-486-3p regulates γ-globin expression in human erythroid cells by directly modulating BCL11A.
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DOI：
10.1371/journal.pone.0060436
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Marziali G
中科院分区：
文献类型：
--
作者：
Lulli V;Romania P;Morsilli O;Cianciulli P;Gabbianelli M;Testa U;Giuliani A;Marziali G
microRNAs（miRNAs）通过抑制mRNA靶点在调节多种细胞过程中发挥关键作用。microRNA的功能相关性已在正常和恶性造血中得到证实。在通过红细胞、巨核细胞、粒细胞和单核细胞途径分析外周血CD 34+造血祖细胞（HPC）的单系无血清液体悬浮单系培养物中的miRNA表达谱时，我们鉴定了miR-486- 3 p主要在红细胞谱系内表达。我们发现miR-486- 3 p通过与BCL 11 A 3′UTR的超长亚型结合来调节BCL 11 A的表达。在红系细胞中过表达miR-486- 3 p导致BCL 11 A蛋白水平降低，与γ-珠蛋白基因表达增加相关，而抑制生理学miR-486- 3 p水平增加BCL 11 A，从而降低γ-珠蛋白表达。因此，调节BCL 11 A表达的miR-486- 3 p可能有助于调节胎儿血红蛋白（HbF），并产生了这样的问题，即该miRNA可能在多大程度上有助于在β-地中海贫血患者中观察到的不同HbF水平。红系细胞，从一小群受重型或中间型β-地中海贫血影响的患者的PB CD 34+细胞分化而来，显示miR-486- 3 p水平显著高于在正常对应物中观察到的水平。重要的是，在这些患者中，miR-486- 3 p表达与HbF合成增加相关。因此，我们的数据表明，miR-486- 3 p可能有助于地中海贫血患者中观察到的不同HbF水平，并可能导致疾病的临床严重程度。
MicroRNAs (miRNAs) play key roles in modulating a variety of cellular processes through repression of mRNAs target. The functional relevance of microRNAs has been proven in normal and malignant hematopoiesis. While analyzing miRNAs expression profile in unilineage serum-free liquid suspension unilineage cultures of peripheral blood CD34+ hematopoietic progenitor cells (HPCs) through the erythroid, megakaryocytic, granulocytic and monocytic pathways, we identified miR-486-3p as mainly expressed within the erythroid lineage. We showed that miR-486-3p regulates BCL11A expression by binding to the extra-long isoform of BCL11A 3′UTR. Overexpression of miR-486-3p in erythroid cells resulted in reduced BCL11A protein levels, associated to increased expression of γ-globin gene, whereas inhibition of physiological miR-486-3p levels increased BCL11A and, consequently, reduced γ-globin expression. Thus, miR-486-3p regulating BCL11A expression might contributes to fetal hemoglobin (HbF) modulation and arise the question as to what extent this miRNA might contribute to different HbF levels observed among β-thalassemia patients. Erythroid cells, differentiated from PB CD34+ cells of a small cohort of patients affected by major or intermedia β-thalassemia, showed miR-486-3p levels significantly higher than those observed in normal counterpart. Importantly, in these patients, miR-486-3p expression correlates with increased HbF synthesis. Thus, our data indicate that miR-486-3p might contribute to different HbF levels observed among thalassemic patients and, possibly, to the clinical severity of the disease.
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DOI：
10.3324/haematol.2009.018259
发表时间：
2010-08-01
期刊：
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
影响因子：
--
作者：
Gabbianelli, Marco;Testa, Ugo;Peschle, Cesare
通讯作者：
Peschle, Cesare
影响因子：
20.3
作者：
Kiefer, Christine M.;Lee, Jongjoo;Dean, Ann
通讯作者：
Dean, Ann
影响因子：
3.2
作者：
Garzon, Ramiro;Croce, Carlo M.
通讯作者：
Croce, Carlo M.
DOI：
10.3324/haematol.2008.002345
发表时间：
2009-04-01
期刊：
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
影响因子：
--
作者：
Felli, Nadia;Pedini, Francesca;Marziali, Giovanna
通讯作者：
Marziali, Giovanna
影响因子：
20.3
作者：
Jiang, Jie;Best, Steve;Thein, Swee Lay
通讯作者：
Thein, Swee Lay