Kojo, S., Tanaka, H., Endo, T.A. et al. Priming of lineage-specifying genes by Bcl11b is required for lineage choice in post-selection thymocytes. Nat Commun 8, 702 (2017). https://doi.org/10.1038/s41467-017-00768-1
Abstract:
T-lineage committed precursor thymocytes are screened by a fate-determination process mediated via T cell receptor (TCR) signals for differentiation into distinct lineages. However, it remains unclear whether any antecedent event is required to couple TCR signals with the transcriptional program governing lineage decisions. Here we show that Bcl11b, known as a T-lineage commitment factor, is essential for proper expression of ThPOK and Runx3, central regulators for the CD4-helper/CD8-cytotoxic lineage choice. Loss of Bcl11b results in random expression of these factors and, thereby, lineage scrambling that is disconnected from TCR restriction by MHC. Initial Thpok repression by Bcl11b prior to the pre-selection stage is independent of a known silencer for Thpok, and requires the last zinc-finger motif in Bcl11b protein, which by contrast is dispensable for T-lineage commitment. Collectively, our findings shed new light on the function of Bcl11b in priming lineage-specifying genes to integrate TCR signals into subsequent transcriptional regulatory mechanisms.
License type:
http://creativecommons.org/licenses/by/4.0/
Funding Info:
We thank C. Miyamoto and R. Chihara for mouse genotyping, N. Yoza for cell sorting, T. Ishikura for ES cell aggregation, Y. Iizuka for microinjection of RNA for CRISPR/Cas9 mediated genome editing. We are grateful to Dr Thomas Boehm for helpful suggestion on analyses of lamprey genome and Dr Eugene Oltz for critical reading of the manuscript. This work was supported by JSPS KAKENHI Grant Number JP 21229008 (I.T.), JP 26293109 (I.T.) and JP 22021045 (I.T.), the Uehara Memorial Foundation (I.T.), Takeda Science Foundation (I.T.) the National Institutes of Health grant R01AI 097244-01A1 (T.E.).