Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL.
The Gene Development and Environment Pediatric Research Institute, Pediatric Hemato-Oncology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
Blood. 2019 Nov 7;134(19):1619-1631. doi: 10.1182/blood.2019001234.
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 Gata1s mice. 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 upregulation of Gata2 and 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 Gata2 and Runx1 genes. Consistent with the observation that overexpression of GATA2 has been reported to impair erythropoiesis, we found that haploinsufficiency of Gata2 rescued the erythroid defects of Gata1s fetuses. Together, our integrated genomic analysis of transcriptomic and epigenetic signatures reveals that, Gata1 mice 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.
GATA1 基因突变导致 GATA1s 异构体的表达，该异构体缺乏 GATA1 的 N 端，可见于 Diamond-Blackfan 贫血（DBA）患者。在努力更好地了解 GATA1s 与 DBA 之间的联系时，我们全面研究了 Gata1s 小鼠的红细胞生成。卵黄囊和胎儿肝脏造血的缺陷包括终端成熟受损和红细胞祖细胞数量减少。RNA 测序显示，N 端缺失会改变红细胞和巨核细胞的基因表达模式，包括 Gata2 和 Runx1 的异常上调。在 GATA1 的 N 端缺失时，在红细胞祖细胞中发现了全局 H3K27 甲基化的失调。染色质结合测定显示，尽管 GATA1 和 GATA1s 的占据相似，但 Gata2 和 Runx1 基因的调控元件处的 H3K27me3 显著减少。与过表达 GATA2 已被报道会损害红细胞生成的观察结果一致，我们发现 Gata2 的杂合不足可挽救 Gata1s 胎儿的红细胞缺陷。综合我们对转录组和表观遗传特征的基因组分析表明，Gata1 小鼠为 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。
