Journal
ELIFE
Volume 10, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.68227
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Funding
- Japan Society for the Promotion of Science [16K08848, JP19H03692, 17H05802, JP20K07730]
- Uehara Memorial Foundation
- Naito Foundation
- Takeda Science Foundation
- Yasuda Medical Foundation
- SENSHIN Medical Research Foundation
- Daiichi Sankyo Foundation of Life Science
- Tokyo Biochemical Research Foundation
- Princess Takamatsu Cancer Research Fund
- Mitsubishi Foundation
- Tokai University School of Medicine Research Aid
- Grants-in-Aid for Scientific Research [17H05802, 16K08848] Funding Source: KAKEN
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The study identified LMO2 as a key player in the survival and maintenance of T-lineage potential in T-cell progenitors by regulating the expression of Bcl11a and Tcf7. Pro-B cells without T-lineage potential failed to activate Tcf7, and deletion of LMO2 resulted in the loss of T-lineage potential.
Notch signaling primarily determines T-cell fate. However, the molecular mechanisms underlying the maintenance of T-lineage potential in pre-thymic progenitors remain unclear. Here, we established two murine Ebf1-deficient pro-B cell lines, with and without T-lineage potential. The latter expressed lower levels of Lmo2; their potential was restored via ectopic expression of Lmo2. Conversely, the CRISPR/Cas9-mediated deletion of Lmo2 resulted in the loss of the T-lineage potential. Introduction of Bcl2 rescued massive cell death of Notch-stimulated pro-B cells without efficient LMO2-driven Bcl11a expression but was not sufficient to retain their T-lineage potential. Pro-B cells without T-lineage potential failed to activate Tcf7 due to DNA methylation; Tcf7 transduction restored this capacity. Moreover, direct binding of LMO2 to the Bcl11a and Tcf7 loci was observed. Altogether, our results highlight LMO2 as a crucial player in the survival and maintenance of T-lineage potential in T-cell progenitors via the regulation of the expression of Bcl11a and Tcf7.
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