title: Asynchronous combinatorial action of four regulatory factors activates Bcl11b for T cell commitment.
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.
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
authors.forename: Hao Yuan
authors.initials: HY
authors.lastname: Kueh
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Yui
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
authors.forename: Kenneth K H
authors.initials: KK
authors.lastname: Ng
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
authors.forename: Shirley S
authors.initials: SS
authors.lastname: Pease
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
authors.forename: Jingli A
authors.initials: JA
authors.lastname: Zhang
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
authors.forename: Sagar S
authors.initials: SS
authors.lastname: Damle
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
authors.forename: George
authors.initials: G
authors.lastname: Freedman
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
authors.forename: Sharmayne
authors.initials: S
authors.lastname: Siu
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Irwin D
authors.initials: ID
authors.lastname: Bernstein
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.|Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Elowitz
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
authors.forename: Ellen V
authors.identifier: 0000-0002-3901-347X
authors.initials: EV
authors.lastname: Rothenberg
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D058948:Cell Tracking; D002478:Cells, Cultured; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism*; D038041:Lymphopoiesis / Q000235:genetics*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051880:Receptors, Notch / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D059010:Single-Cell Analysis; D013601:T-Lymphocytes / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C511143:Bcl11b protein, mouse; D050676:Core Binding Factor Alpha 2 Subunit; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; D051880:Receptors, Notch; D012097:Repressor Proteins; C493726:Runx1 protein, mouse; D025521:Tumor Suppressor Proteins