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

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)112-126
Number of pages15
JournalGenes and Development
Volume32
Issue number2
DOIs
Publication statusPublished - 15-01-2018
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

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