Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Cell Differentiation / genetics
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Cell Lineage / genetics
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Cell Tracking
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Cells, Cultured
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Core Binding Factor Alpha 2 Subunit / genetics
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Core Binding Factor Alpha 2 Subunit / metabolism*
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GATA3 Transcription Factor / genetics
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GATA3 Transcription Factor / metabolism*
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Gene Expression Regulation, Developmental*
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Hepatocyte Nuclear Factor 1-alpha / genetics
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Hepatocyte Nuclear Factor 1-alpha / metabolism*
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Lymphopoiesis / genetics*
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Mice
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Mice, 129 Strain
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Mice, Inbred C57BL
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Mice, Transgenic
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Receptors, Notch / metabolism*
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Signal Transduction
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Single-Cell Analysis
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T-Lymphocytes / physiology*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
Substances
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Bcl11b protein, mouse
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Core Binding Factor Alpha 2 Subunit
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GATA3 Transcription Factor
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Gata3 protein, mouse
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Hepatocyte Nuclear Factor 1-alpha
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Hnf1a protein, mouse
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Receptors, Notch
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Repressor Proteins
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Runx1 protein, mouse
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Tumor Suppressor Proteins