Three-step transcriptional priming that drives the commitment of multipotent progenitors toward B cells.
Three-step transcriptional priming that drives the commitment of multipotent progenitors toward B cells.
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DOI：
10.1101/gad.309575.117
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发表时间：
2018-01-15
影响因子：
10.5
通讯作者：
Ikawa T
中科院分区：
文献类型：
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作者：
Miyai T;Takano J;Endo TA;Kawakami E;Agata Y;Motomura Y;Kubo M;Kashima Y;Suzuki Y;Kawamoto H;Ikawa T
宫井等人。使用含有他莫昔芬诱导形式的 Id3 的多能祖细胞（其中几乎所有细胞通过撤回 4-OHT 在 6 天内变成 B 细胞）在多能祖细胞向 B 细胞谱系的规范过程中鉴定了三步转录因子网络模型。干细胞的命运是由核心转录因子（TF）和表观遗传修饰精心策划的。尽管控制细胞类型规范的调控基因已被识别，但细胞命运决定过程中的转录回路和调控因子之间的串扰仍然知之甚少。为了识别 B 谱系定型过程中的“延时”TF 网络，我们使用了含有他莫昔芬诱导型 Id3 的多能祖细胞，这是一种体外系统，其中几乎所有细胞只需撤回 4-羟基他莫昔芬 (4-OHT)，即可在 6 天内变成 B 细胞。多个时间点的转录组和表观基因组分析表明~10%–30%的差异表达基因实际上是由核心转录因子控制的，包括E2A、EBF1和PAX5。引人注目的是，我们在关键 TF 程序开始之前发现了意想不到的转录启动。 Nr4a2、Klf4 和 Egr1 等早期基因的抑制严重损害了 B 细胞的生成。整合多个数据集（包括转录组、蛋白质相互作用组和表观基因组图谱），确定了三个代表性转录回路。骨髓中淋巴祖细胞的单细胞 RNA 测序 (RNA-seq) 分析有力地支持了体内 B 细胞谱系多能祖细胞规范过程中的三步 TF 网络模型。因此，我们的研究结果将为研究 B 淋巴细胞的正常和肿瘤发育提供蓝图。
Miyai et al. used multipotent progenitors harboring a tamoxifen-inducible form of Id3—where virtually all cells became B cells within 6 d by withdrawing 4-OHT—to identify a three-step transcription factor network model during specification of multipotent progenitors toward the B-cell lineage. Stem cell fate is orchestrated by core transcription factors (TFs) and epigenetic modifications. Although regulatory genes that control cell type specification are identified, the transcriptional circuit and the cross-talk among regulatory factors during cell fate decisions remain poorly understood. To identify the “time-lapse” TF networks during B-lineage commitment, we used multipotent progenitors harboring a tamoxifen-inducible form of Id3, an in vitro system in which virtually all cells became B cells within 6 d by simply withdrawing 4-hydroxytamoxifen (4-OHT). Transcriptome and epigenome analysis at multiple time points revealed that ∼10%–30% of differentially expressed genes were virtually controlled by the core TFs, including E2A, EBF1, and PAX5. Strikingly, we found unexpected transcriptional priming before the onset of the key TF program. Inhibition of the immediate early genes such as Nr4a2, Klf4, and Egr1 severely impaired the generation of B cells. Integration of multiple data sets, including transcriptome, protein interactome, and epigenome profiles, identified three representative transcriptional circuits. Single-cell RNA sequencing (RNA-seq) analysis of lymphoid progenitors in bone marrow strongly supported the three-step TF network model during specification of multipotent progenitors toward B-cell lineage in vivo. Thus, our findings will provide a blueprint for studying the normal and neoplastic development of B lymphocytes.
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