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Three-step transcriptional priming that drives the commitment of multipotent
progenitors toward B cells
#MMPMID29440259
Miyai T
; Takano J
; Endo TA
; Kawakami E
; Agata Y
; Motomura Y
; Kubo M
; Kashima Y
; Suzuki Y
; Kawamoto H
; Ikawa T
Genes Dev
2018[Jan]; 32
(2
): 112-126
PMID29440259
show ga
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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