Tracking the gene expression programs and clonal relationships that underlie mast, myeloid, and T lineage specification from stem cells.

Cell systems Pub Date : 2024-12-18 Epub Date: 2024-11-29 DOI:10.1016/j.cels.2024.11.001
Yale S Michaels, Matthew C Major, Becca Bonham-Carter, Jingqi Zhang, Tiam Heydari, John M Edgar, Mona M Siu, Laura Greenstreet, Roser Vilarrasa-Blasi, Seungjoon Kim, Elizabeth L Castle, Aden Forrow, M Iliana Ibanez-Rios, Carla Zimmerman, Yvonne Chung, Tara Stach, Nico Werschler, David J H F Knapp, Roser Vento-Tormo, Geoffrey Schiebinger, Peter W Zandstra
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Abstract

T cells develop from hematopoietic progenitors in the thymus and protect against pathogens and cancer. However, the emergence of human T cell-competent blood progenitors and their subsequent specification to the T lineage have been challenging to capture in real time. Here, we leveraged a pluripotent stem cell differentiation system to understand the transcriptional dynamics and cell fate restriction events that underlie this critical developmental process. Time-resolved single-cell RNA sequencing revealed that downregulation of the multipotent hematopoietic program, upregulation of >90 lineage-associated transcription factors, and cell-cycle exit all occur within a highly coordinated developmental window. Gene-regulatory network inference uncovered a role for YBX1 in T lineage specification. We mapped the differentiation cell fate hierarchy using transcribed lineage barcoding and discovered that mast and myeloid potential bifurcate from each other early in hematopoiesis, upstream of T lineage restriction. Our systems-level analyses provide a quantitative, time-resolved model of human T cell fate specification. A record of this paper's transparent peer review process is included in the supplemental information.

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跟踪基因表达程序和克隆关系的基础上,肥大,髓系,和T谱系规范的干细胞。
T细胞由胸腺内的造血祖细胞发育而来,保护机体免受病原体和癌症的侵袭。然而,人类T细胞能力造血祖细胞的出现及其随后对T谱系的规范一直是实时捕获的挑战。在这里,我们利用多能干细胞分化系统来了解这一关键发育过程背后的转录动力学和细胞命运限制事件。时间分辨单细胞RNA测序显示,多能造血程序的下调、bbb90谱系相关转录因子的上调和细胞周期退出都发生在一个高度协调的发育窗口内。基因调控网络推断揭示了YBX1在T谱系规范中的作用。我们利用转录谱系条形码绘制了分化细胞命运等级图,发现在造血早期,在T谱系限制的上游,肥大细胞和髓细胞电位彼此分叉。我们的系统级分析提供了人类T细胞命运规范的定量、时间分辨模型。本文的透明同行评议过程记录包含在补充信息中。
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