Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 23, Pages 5800-5807Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1610617114
Keywords
Bcl11b; Notch-delta signaling; PU.1; E2A; commitment
Categories
Funding
- NIH New Innovator Award [DP2GM111100]
- NIH [R01HD073113, K99HL119638A, RC2CA148278, R01CA90233, R01AI083514, R01AI95943]
- L. A. Garfinkle Memorial Laboratory Fund
- Al Sherman Foundation
- Caltech-City of Hope Biomedical Research Initiative
- Albert Billings Ruddock Professorship
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T-cell development from hematopoietic progenitors depends on multiple transcription factors, mobilized and modulated by intrathymic Notch signaling. Key aspects of T-cell specification network architecture have been illuminated through recent reports defining roles of transcription factors PU.1, GATA-3, and E2A, their interactions with Notch signaling, and roles of Runx1, TCF-1, and Hes1, providing bases for a comprehensively updated model of the T-cell specification gene regulatory network presented herein. However, the role of lineage commitment factor Bcl11b has been unclear. We use self-organizing maps on 63 RNA-seq datasets from normal and perturbed T-cell development to identify functional targets of Bcl11b during commitment and relate them to other regulomes. We show that both activation and repression target genes can be bound by Bcl11b in vivo, and that Bcl11b effects overlap with E2A-dependent effects. The newly clarified role of Bcl11b distinguishes discrete components of commitment, resolving how innate lymphoid, myeloid, and dendritic, and B-cell fate alternatives are excluded by different mechanisms.
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