Mutations in GATA1, which lead to expression of the GATA1s isoform that lacks the GATA1 N-terminus, are seen in patients with Diamond-Blackfan Anemia (DBA). In our efforts to better understand the connection between GATA1s and DBA, we comprehensively studied erythropoiesis in Gata1smice. Defects in yolks sac and fetal liver hematopoiesis included impaired terminal maturation and reduced numbers of erythroid progenitors. RNA-sequencing revealed that both erythroid and megakaryocytic gene expression patterns were altered by the loss of the N-terminus, including aberrant up-regulation of Gata2and Runx1 Dysregulation of global H3K27 methylation was found in the erythroid progenitors upon loss of N-terminus of GATA1. Chromatin binding assays revealed that, despite similar occupancy of GATA1 and GATA1s, there was a striking reduction of H3K27me3 at regulatory elements of the Gata2and Runx1genes. Consistent with the observation that overexpression of GATA2 has been reported to impair erythropoiesis, we found that haploinsufficiency of Gata2rescued the erythroid defects of Gata1sfetuses. Together, our integrated genomic analysis of transcriptomic and epigenetic signatures reveals that, Gata1smice provide novel insights into the role of the N-terminus of GATA1 in transcriptional regulation and red blood cell maturation which may potentially be useful for DBA patients.

中文翻译：

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染色质占有率和表观遗传分析揭示了对 GATA1 N 末端在红细胞生成中功能的新见解

在 Diamond-Blackfan 贫血 (DBA) 患者中可以看到 GATA1 的突变，导致缺乏 GATA1 N 末端的 GATA1s 同种型的表达。为了更好地理解 GATA1s 和 DBA 之间的联系，我们全面研究了 Gata1smice 的红细胞生成。卵黄囊和胎儿肝脏造血的缺陷包括终末成熟受损和红系祖细胞数量减少。RNA测序显示红系和巨核细胞基因表达模式都因N端的丢失而改变，包括Gata2和Runx1的异常上调，在GATA1的N端丢失后，在红系祖细胞中发现了全局H3K27甲基化的失调. 染色质结合分析表明，尽管 GATA1 和 GATA1s 的占有率相似，Gata2 和 Runx1 基因的调控元件中 H3K27me3 显着减少。与据报道 GATA2 过表达会损害红细胞生成的观察结果一致，我们发现 Gata2 的单倍体不足挽救了 Gata1 胎儿的红系缺陷。总之，我们对转录组和表观遗传特征的综合基因组分析表明，Gata1smice 为 GATA1 的 N 端在转录调控和红细胞成熟中的作用提供了新的见解，这可能对 DBA 患者有用。