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Transcriptional regulatory network controlling the ontogeny of hematopoietic stem cells.
Genes & Development ( IF 7.5 ) Pub Date : 2020-07-01 , DOI: 10.1101/gad.338202.120
Peng Gao 1 , Changya Chen 1 , Elizabeth D Howell 2, 3 , Yan Li 2 , Joanna Tober 2 , Yasin Uzun 1 , Bing He 1 , Long Gao 4 , Qin Zhu 5 , Arndt F Siekmann 2 , Nancy A Speck 2, 6 , Kai Tan 1, 2, 4, 7
Affiliation  

Hematopoietic stem cell (HSC) ontogeny is accompanied by dynamic changes in gene regulatory networks. We performed RNA-seq and histone mark ChIP-seq to define the transcriptomes and epigenomes of cells representing key developmental stages of HSC ontogeny in mice. The five populations analyzed were embryonic day 10.5 (E10.5) endothelium and hemogenic endothelium from the major arteries, an enriched population of prehematopoietic stem cells (pre-HSCs), fetal liver HSCs, and adult bone marrow HSCs. Using epigenetic signatures, we identified enhancers for each developmental stage. Only 12% of enhancers are primed, and 78% are active, suggesting the vast majority of enhancers are established de novo without prior priming in earlier stages. We constructed developmental stage-specific transcriptional regulatory networks by linking enhancers and predicted bound transcription factors to their target promoters using a novel computational algorithm, target inference via physical connection (TIPC). TIPC predicted known transcriptional regulators for the endothelial-to-hematopoietic transition, validating our overall approach, and identified putative novel transcription factors, including the broadly expressed transcription factors SP3 and MAZ. Finally, we validated a role for SP3 and MAZ in the formation of hemogenic endothelium. Our data and computational analyses provide a useful resource for uncovering regulators of HSC formation.

中文翻译:

控制造血干细胞个体发育的转录调控网络。

造血干细胞 (HSC) 个体发育伴随着基因调控网络的动态变化。我们进行了 RNA-seq 和组蛋白标记 ChIP-seq 来定义代表小鼠 HSC 个体发育关键发育阶段的细胞的转录组和表观基因组。分析的五个群体是来自主要动脉的胚胎第 10.5 天 (E10.5) 内皮细胞和生血内皮细胞、造血前干细胞 (pre-HSCs)、胎儿肝脏 HSCs 和成人骨髓 HSCs 的丰富群体。使用表观遗传特征,我们确定了每个发育阶段的增强子。只有 12% 的增强子被启动,而 78% 是活跃的,这表明绝大多数增强子是在没有在早期阶段预先启动的情况下从头建立的。我们通过使用一种新的计算算法,通过物理连接进行目标推断 (TIPC),将增强子和预测的结合转录因子与其目标启动子联系起来,构建了发育阶段特定的转录调控网络。TIPC 预测了内皮细胞到造血细胞转变的已知转录调节因子,验证了我们的整体方法,并确定了推定的新转录因子,包括广泛表达的转录因子 SP3 和 MAZ。最后,我们验证了 SP3 和 MAZ 在造血内皮形成中的作用。我们的数据和计算分析为揭示 HSC 形成的监管机构提供了有用的资源。TIPC 预测了内皮细胞到造血细胞转变的已知转录调节因子,验证了我们的整体方法,并确定了推定的新转录因子,包括广泛表达的转录因子 SP3 和 MAZ。最后,我们验证了 SP3 和 MAZ 在造血内皮形成中的作用。我们的数据和计算分析为揭示 HSC 形成的监管机构提供了有用的资源。TIPC 预测了内皮细胞到造血细胞转变的已知转录调节因子,验证了我们的整体方法,并确定了推定的新转录因子,包括广泛表达的转录因子 SP3 和 MAZ。最后,我们验证了 SP3 和 MAZ 在造血内皮形成中的作用。我们的数据和计算分析为揭示 HSC 形成的监管机构提供了有用的资源。
更新日期:2020-07-01
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