The order of expression of transcription factors directs hierarchical specification of hematopoietic lineages.
The mechanism of lineage specification in multipotent stem cells has not been fully understood. We recently isolated progenitors with the eosinophil, basophil, or mast cell lineage potential, all of which originate from granulocyte/monocyte progenitors (GMPs). By using these prospectively purified progenitors, we show here that the expression timing of GATA-2 and CCAAT enhancer-binding protein alpha (C/EBPalpha) can differentially control their lineage commitment. The expression of GATA-2 instructed C/EBPalpha-expressing GMPs to commit exclusively into the eosinophil lineage, while it induced basophil and/or mast cell lineage commitment if C/EBPalpha was suppressed at the GMP stage. Furthermore, simply by switching the order of C/EBPalpha and GATA-2 transduction, even lymphoid-committed progenitors recaptured these developmental processes to be reprogrammed into each of these lineages. We propose that the order of expression of key transcription factors is critical for their interplay to selectively drive lineage specification programs, by which stem cells could generate multiple lineage cells in a hierarchical manner.
Iwasaki
Hiromi
H
Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan.
Mizuno
Shin-ichi
S
Arinobu
Yojiro
Y
Ozawa
Hidetoshi
H
Mori
Yasuo
Y
Shigematsu
Hirokazu
H
Takatsu
Kiyoshi
K
Tenen
Daniel G
DG
Akashi
Koichi
K
D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D050989:GATA2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006098:Granulocytes / Q000166:cytology / Q000378:metabolism; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D008407:Mast Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000378:metabolism
D022763:CCAAT-Enhancer-Binding Protein-alpha; D050989:GATA2 Transcription Factor; C494712:Gata2 protein, mouse