Defective erythropoiesis caused by mutations of the thyroid hormone receptor α gene.
Defective erythropoiesis caused by mutations of the thyroid hormone receptor α gene.
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DOI：
10.1371/journal.pgen.1006991
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发表时间：
2017-09
期刊：
影响因子：
4.5
通讯作者：
Cheng SY
中科院分区：
文献类型：
--
作者：
Park S;Han CR;Park JW;Zhao L;Zhu X;Willingham M;Bodine DM;Cheng SY
具有THRA基因突变的患者表现出甲状腺功能减退症的典型特征，包括红系疾病。我们之前创建了一个表达突变TRα1的突变小鼠（表示为PV; Thra 1 PV/+小鼠），该小鼠忠实地再现了患者中观察到的经典甲状腺功能减退症。使用Thra 1 PV/+小鼠，我们探讨了TRα 1 PV突变体如何引起红细胞生成异常。Thra 1 PV/+小鼠表现出与患者报告相似的异常红细胞指数。Thra 1 PV/+小鼠骨髓中的总骨髓细胞和红细胞祖细胞明显减少。体外终末分化试验显示Thra 1 PV/+小鼠的成熟红细胞显著减少。在野生型小鼠中，红细胞系中祖细胞的克隆形成潜力被甲状腺激素（T3）刺激，表明T3可以直接加速祖细胞向成熟红细胞的分化。基因表达谱分析显示，Thra 1 PV/+小鼠骨髓细胞中红细胞生成的关键调控因子加塔-1基因及其调控基因Klf 1、β-珠蛋白、dematin基因、CAII、band 3和eALAS基因表达降低。进一步阐明了加塔-1基因是一个T3直接调控的基因，TRα 1 PV通过抑制加塔-1基因及其调控基因而抑制红细胞生成。这些结果为TRα1突变体如何导致THRA基因突变患者红系异常提供了新的见解。重要的是，Thra 1 PV/+小鼠可以作为临床前小鼠模型，以确定治疗红系疾病的新分子靶点。具有THRA基因突变的患者表现出红系疾病。红系异常的分子发病机制知之甚少。在表达显性阴性突变TRα 1 PV的Thra 1 PV/+小鼠中，我们发现与患者相似的异常红细胞指数。Thra 1 PV/+小鼠的总骨髓细胞、红细胞祖细胞的克隆形成能力和红细胞的终末分化显著降低。我们阐明了红系关键基因加塔-1受TRα1直接正调控。Thra 1 PV/+小鼠的红系缺陷至少部分归因于TRα 1 PV介导的加塔-1基因及其下游靶基因的抑制。过表达加塔-1挽救受损的终末分化。我们的研究阐明了TRα1突变体引起患者红系疾病的分子机制。目前的研究表明，针对GATA 1的疗法可以作为治疗红细胞异常患者的潜在靶点进行测试。
Patients with mutations of the THRA gene exhibit classical features of hypothyroidism, including erythroid disorders. We previously created a mutant mouse expressing a mutated TRα1 (denoted as PV; Thra1PV/+ mouse) that faithfully reproduces the classical hypothyroidism seen in patients. Using Thra1PV/+ mice, we explored how the TRα1PV mutant acted to cause abnormalities in erythropoiesis. Thra1PV/+ mice exhibited abnormal red blood cell indices similarly as reported for patients. The total bone marrow cells and erythrocytic progenitors were markedly reduced in the bone marrow of Thra1PV/+ mice. In vitro terminal differentiation assays showed a significant reduction of mature erythrocytes in Thra1PV/+ mice. In wild-type mice, the clonogenic potential of progenitors in the erythrocytic lineage was stimulated by thyroid hormone (T3), suggesting that T3 could directly accelerate the differentiation of progenitors to mature erythrocytes. Analysis of gene expression profiles showed that the key regulator of erythropoiesis, the Gata-1 gene, and its regulated genes, such as the Klf1, β-globin, dematin genes, CAII, band3 and eALAS genes, involved in the maturation of erythrocytes, was decreased in the bone marrow cells of Thra1PV/+ mice. We further elucidated that the Gata-1 gene was a T3-directly regulated gene and that TRα1PV could impair erythropoiesis via repression of the Gata-1 gene and its regulated genes. These results provide new insights into how TRα1 mutants acted to cause erythroid abnormalities in patients with mutations of the THRA gene. Importantly, the Thra1PV/+ mouse could serve as a preclinical mouse model to identify novel molecular targets for treatment of erythroid disorders. Patients with mutations of the THRA gene exhibit erythroid disorders. The molecular pathogenesis underlying erythroid abnormalities is poorly understood. In Thra1PV/+ mice expressing a dominant negative mutant TRα1PV, we found abnormal red blood cell indices similar to patients. Total bone marrow cells, the clonogenic potential of erythrocytic progenitors, and terminal differentiation of erythrocytes were markedly decreased in Thra1PV/+ mice. We elucidated that Gata-1, a key erythroid gene, was directly positively regulated by TRα1. The erythroid defects in Thra1PV/+ mice were due, at least partly, to the TRα1PV-mediated suppression of the Gata-1 gene and its down-stream target genes. Over-expression of Gata-1 rescued impaired terminal differentiation. Our studies elucidated molecular mechanisms by which TRα1 mutants caused erythroid disorders in patients. The present study suggests that therapies aimed at GATA1 could be tested as a potential target in treating erythroid abnormalities in patients.
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