Three-step transcriptional priming that drives the commitment of multipotent progenitors toward B cells

Tomohiro Miyai, Junichiro Takano, Takaho A. Endo, Eiryo Kawakami, Yasutoshi Agata, Yasutaka Motomura, Masato Kubo, Yukie Kashima, Yutaka Suzuki, Hiroshi Kawamoto, Tomokatsu Ikawa

研究成果: Article査読

15 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)112-126
ページ数15
ジャーナルGenes and Development
32
2
DOI
出版ステータスPublished - 15-01-2018
外部発表はい

All Science Journal Classification (ASJC) codes

  • 遺伝学
  • 発生生物学

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