Defining the Minimal Factors Required for Erythropoiesis through Direct Lineage Conversion.
Defining the Minimal Factors Required for Erythropoiesis through Direct Lineage Conversion.
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DOI：
10.1016/j.celrep.2016.05.027
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发表时间：
2016-06-14
期刊：
影响因子：
8.8
通讯作者：
Flygare J
中科院分区：
文献类型：
--
作者：
Capellera-Garcia S;Pulecio J;Dhulipala K;Siva K;Rayon-Estrada V;Singbrant S;Sommarin MN;Walkley CR;Soneji S;Karlsson G;Raya Á;Sankaran VG;Flygare J
红系细胞的承诺和分化是通过激活一个谱系受限的转录网络进行的，该网络由一组特征明确的基因编排。然而，指导红细胞(RBC)发育所需的最小一组因子仍未确定。我们使用了一种转录因子的筛选，允许从成纤维细胞直接谱系重编程为诱导的红系祖细胞/前体(IEP)。我们发现GATA1、Tal1、Lmo2和c-Myc(GTLM)可以快速地将小鼠和人成纤维细胞直接转化为IEP。小鼠IEP的转录特征主要类似于卵黄囊中原始红系祖细胞的转录特征，而在GTLM鸡尾酒中加入KLF1或Myb导致IEP具有更成人型的珠蛋白表达模式。我们的结果表明，直接血统转换是定义和研究导致红系发育不同波的核心因素的合适平台。GATA1、Tal1、Lmo2和c-Myc将成纤维细胞重编程为红系祖细胞(IEP)IEP基因的表达更接近原始红细胞的表达，而不是确定的红系祖细胞KLF1或Myb过表达诱导IEP成人血红蛋白表达。显示GATA1、Tal1、Lmo2和c-Myc直接将小鼠和人类成纤维细胞转化为红系祖细胞/前体细胞。这一发现定义了一种保守的转录程序，指示哺乳动物的红系细胞命运。
Erythroid cell commitment and differentiation proceed through activation of a lineage-restricted transcriptional network orchestrated by a group of well characterized genes. However, the minimal set of factors necessary for instructing red blood cell (RBC) development remains undefined. We employed a screen for transcription factors allowing direct lineage reprograming from fibroblasts to induced erythroid progenitors/precursors (iEPs). We show that Gata1, Tal1, Lmo2, and c-Myc (GTLM) can rapidly convert murine and human fibroblasts directly to iEPs. The transcriptional signature of murine iEPs resembled mainly that of primitive erythroid progenitors in the yolk sac, whereas addition of Klf1 or Myb to the GTLM cocktail resulted in iEPs with a more adult-type globin expression pattern. Our results demonstrate that direct lineage conversion is a suitable platform for defining and studying the core factors inducing the different waves of erythroid development. Gata1, Tal1, Lmo2, and c-Myc reprogram fibroblasts to erythroid progenitors (iEPs) iEP gene expression is more similar to that of primitive than definitive erythroblasts Klf1 or Myb overexpression induces adult hemoglobin expression in iEPs Capellera-Garcia et al. show that Gata1, Tal1, Lmo2, and c-Myc directly convert murine and human fibroblasts into erythroid progenitor/precursor cells. This finding defines a conserved transcriptional program instructing erythroid cell fate in mammals.