Asynchronous combinatorial action of four regulatory factors activates Bcl11b for T cell commitment

• DOI: 10.1038/ni.3514
• Publication Date: 2016-07-04T15:23:05Z
• Authors: Hao Yuan Kueh; Mary A Yui; Kenneth K H Ng; Shirley S Pease; Jingli A Zhang; Sagar S Damle; George Freedman; Sharmayne Siu; Irwin D Bernstein; Michael B Elowitz; Ellen V Rothenberg
• Keywords: 570; Mice, 129 Strain; Receptors, Notch; Lymphopoiesis; T-Lymphocytes; Tumor Suppressor Proteins; 610; Gene Expression Regulation, Developmental; Cell Differentiation; Mice, Transgenic; GATA3 Transcription Factor; Article; Mice, Inbred C57BL; Repressor Proteins; Mice; Cell Tracking; Core Binding Factor Alpha 2 Subunit; Animals; Cell Lineage; Hepatocyte Nuclear Factor 1-alpha; Single-Cell Analysis; Cells, Cultured; Signal Transduction

During T cell development, multipotent progenitors relinquish competence for other fates and commit to the T cell lineage by turning on Bcl11b, which encodes a transcription factor. To clarify lineage commitment mechanisms, we followed developing T cells at the single-cell level using Bcl11b knock-in fluorescent reporter mice. Notch signaling and Notch-activated transcription factors collaborate to activate Bcl11b expression irrespectively of Notch-dependent proliferation. These inputs work via three distinct, asynchronous mechanisms: an early locus 'poising' function dependent on TCF-1 and GATA-3, a stochastic-permissivity function dependent on Notch signaling, and a separate amplitude-control function dependent on Runx1, a factor already present in multipotent progenitors. Despite their necessity for Bcl11b expression, these inputs act in a stage-specific manner, providing a multitiered mechanism for developmental gene regulation.