College of Pharmacy, Binzhou Medical University, China.
College of Life Science, Yantai University, China.
Biochem Biophys Res Commun. 2024 Jun 30;715:150004. doi: 10.1016/j.bbrc.2024.150004. Epub 2024 Apr 25.
Megakaryopoiesis and platelet production is a complex process that is underpotential regulation at multiple stages. Many long non-coding RNAs (lncRNAs) are distributed in hematopoietic stem cells and platelets. lncRNAs may play important roles as key epigenetic regulators in megakaryocyte differentiation and proplatelet formation. lncRNA NORAD can affect cell ploidy by sequestering PUMILIO proteins, although its direct effect on megakaryocyte differentiation and thrombopoiesis is still unknown. In this study, we demonstrate NORAD RNA is highly expressed in the cytoplasm during megakaryocyte differentiation. Interestingly, we identified for the first time that NORAD has a strong inhibitory effect on megakaryocyte differentiation and proplatelet formation from cultured megakaryocytes. DUSP6/ERK1/2 pathway is activated in response to NORAD knockdown during megakaryocytopoiesis, which is achieved by sequestering PUM2 proteins. Finally, compared with the wild-type control mice, NORAD knockout mice show a faster platelet recovery after severe thrombocytopenia induced by 6 Gy total body irradiation. These findings demonstrate lncRNA NORAD has a key role in regulating megakaryocyte differentiation and thrombopoiesis, which provides a promising molecular target for the treatment of platelet-related diseases such as severe thrombocytopenia.
巨核细胞生成和血小板生成是一个复杂的过程，在多个阶段受到潜在调节。许多长链非编码 RNA（lncRNA）分布在造血干细胞和血小板中。lncRNA 可能作为关键的表观遗传调节剂，在巨核细胞分化和前血小板形成中发挥重要作用。lncRNA NORAD 可以通过结合 PUMILIO 蛋白来影响细胞倍性，尽管其对巨核细胞分化和血小板生成的直接影响仍不清楚。在本研究中，我们发现在巨核细胞分化过程中 NORAD RNA 高度表达于细胞质中。有趣的是，我们首次发现 NORAD 对体外培养的巨核细胞的巨核细胞分化和前血小板形成具有强烈的抑制作用。在巨核细胞生成过程中，NORAD 敲低会激活 DUSP6/ERK1/2 通路，这是通过结合 PUM2 蛋白来实现的。最后，与野生型对照小鼠相比，NORAD 敲除小鼠在 6Gy 全身照射诱导的严重血小板减少后血小板恢复更快。这些发现表明 lncRNA NORAD 在调节巨核细胞分化和血小板生成中起关键作用，为治疗血小板相关疾病（如严重血小板减少症）提供了有前途的分子靶点。
