Pluripotent stem cells reveal erythroid-specific activities of the GATA1 N-terminus
Pluripotent stem cells reveal erythroid-specific activities of the GATA1 N-terminus
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DOI：
10.1172/jci75714
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发表时间：
2015-03-01
影响因子：
15.9
通讯作者：
Chou, Stella T.
中科院分区：
文献类型：
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作者：
Byrska-Bishop, Marta;VanDorn, Daniel;Chou, Stella T.
生殖系GATA 1突变导致产生称为GATA 1 s（其中s表示短）的氨基截短蛋白，导致先天性再生障碍性贫血。在21三体患者中，类似的体细胞GATA 1产生突变促进一过性骨髓增生性疾病和急性巨核细胞白血病。在这里，我们证明，诱导多能干细胞（iPSC）与GATA 1截短突变患者表现出受损的红细胞潜能，但增强巨核细胞和骨髓生成，概括了相关疾病的主要表型。同样，在发育停滞的GATA 1缺陷型小鼠巨核细胞-红系祖细胞来源于小鼠胚胎干细胞（ESC），GATA 1的表达促进巨核细胞，但不是红细胞生成。转录组分析显示GATA 1激活造血祖细胞群体内红系特异性基因的能力存在选择性缺陷。虽然其DNA结合域是完整的，染色质免疫沉淀研究表明，GATA 1 s在特定的红细胞调节区的结合受损，而在许多非红细胞位点，包括巨核细胞和髓样靶基因的结合是正常的。总之，这些观察结果表明，谱系特异性GATA 1辅因子协会是必不可少的正常染色质占用，并提供GATA 1 s突变如何导致人类疾病的机制的见解。更广泛地说，我们的研究强调了ESC和iPSC在概括和研究疾病表型方面的价值。
Germline GATA1 mutations that result in the production of an amino-truncated protein termed GATA1s (where s indicates short) cause congenital hypoplastic anemia. In patients with trisomy 21, similar somatic GATA1s-producing mutations promote transient myeloproliferative disease and acute megakaryoblastic leukemia. Here, we demonstrate that induced pluripotent stem cells (iPSCs) from patients with GATA1-truncating mutations exhibit impaired erythroid potential, but enhanced megakaryopoiesis and myelopoiesis, recapitulating the major phenotypes of the associated diseases. Similarly, in developmentally arrested GATA1-deficient murine megakaryocyte-erythroid progenitors derived from murine embryonic stem cells (ESCs), expression of GATA1s promoted megakaryopoiesis, but not erythropoiesis. Transcriptome analysis revealed a selective deficiency in the ability of GATA1s to activate erythroid-specific genes within populations of hematopoietic progenitors. Although its DNA-binding domain was intact, chromatin immunoprecipitation studies showed that GATA1s binding at specific erythroid regulatory regions was impaired, while binding at many nonerythroid sites, including megakaryocytic and myeloid target genes, was normal. Together, these observations indicate that lineage-specific GATA1 cofactor associations are essential for normal chromatin occupancy and provide mechanistic insights into how GATA1s mutations cause human disease. More broadly, our studies underscore the value of ESCs and iPSCs to recapitulate and study disease phenotypes.