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Transcriptional Establishment of Cell-Type Identity: Dynamics and Causal Mechanisms of T-Cell Lineage Commitment

Rothenberg, Ellen V. and Champhekar, Ameya and Damle, Sagar and Del Real, Marissa Morales and Kueh, Hao Yuan and Li, Long and Yui, Mary A. (2013) Transcriptional Establishment of Cell-Type Identity: Dynamics and Causal Mechanisms of T-Cell Lineage Commitment. Cold Spring Harbor Symposia on Quantitative Biology, 78 . pp. 1-11. ISSN 0091-7451. PMCID PMC3990665. doi:10.1101/sqb.2013.78.020271.

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Precursor cell entry into the T-cell developmental pathway can be divided into two phases by the closure of T-lineage commitment. As cells decide against the last alternative options to the T-cell fate, they turn on the transcription factor Bcl11b and silence expression of a group of multipotent progenitor regulatory factors that include hematopoietic transcription factor PU.1. Functional perturbation tests show that Bcl11b is needed for commitment while PU.1 actively participates in keeping open access to alternative fates, until it is silenced; however, PU.1 and Bcl11b both contribute positively to T-cell development. Our recent work reviewed here sheds light on the transcriptional regulatory network that determines the timing and irreversibility of Bcl11b activation, the ways that Notch signaling from the thymic microenvironment restricts the action of PU.1 to prevent it from diverting cells to non-T fates, and the target genes that PU.1 still regulates under the influence of Notch signaling to contribute to T-cell generation. We argue that T-cell development depends on the sequential operation of two interlaced, but mutually antagonistic, gene regulatory networks, one initially supporting expansion before commitment and the other imposing a "terminal" differentiation process on committed cells.

Item Type:Article
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URLURL TypeDescription CentralArticle
Rothenberg, Ellen V.0000-0002-3901-347X
Kueh, Hao Yuan0000-0001-6272-6673
Yui, Mary A.0000-0002-3136-2181
Additional Information:© 2013 Cold Spring Harbor Laboratory Press. Published online October 17, 2013 in advance of the print volume. We thank our colleagues Michael Elowitz (Caltech), Eric Davidson (Caltech), Carsten Peterson (Lund University), Vijay Chickarmane (Caltech), and Erica Manesso (Lund University) for advice and stimulating theoretical discussions; Marei Dose and Fotini Gounari (University of Chicago) for sharing important ChIP-seq data sets; Irwin Bernstein (Fred Hutchinson Cancer Research Center) for advice and donating DL1-Fc; Stephen Nutt (Walter & Eliza Hall Institute), Mark Leid (Oregon State Health SciencesCenter), and Pentao Liu (Cambridge University) for valuable transgenic mouse strains; and Shirley Pease and the Caltech Genetically Modified Mouse Service for generation of new fluorescent reporter mouse strains, all of whom contributed to the experiments reviewed here. We are also indebted to Rochelle Diamond for outstanding laboratory management; Robert Butler, Ni Feng, Maria Lerica Gutierrez Quiloan, and Edward Hernandez for technical support; Diana Perez, Janice Grimm, and Josh Verceles for help with cell sorting; and Ingrid Soto for mouse care. Our work was made possible by support from National Institutes of Health (NIH) grants to E.V.R. (RC2 CA148278, R33 HL089123, R01 CA090233, R01 AI083514, and R01 AI095943) and to M.A.Y. (R01 AI064590), a Cancer Research Institute-Irvington Fellowship to H.Y.K., the Albert Billings Ruddock Professorship to E.V.R., the Al Sherman Foundation, and the Louis A. Garfinkle Memorial Laboratory Fund.
Funding AgencyGrant Number
NIHRC2 CA148278
NIHR33 HL089123
NIHR01 CA090233
NIHR01 AI083514
NIHR01 AI095943
NIHR01 AI064590
Cancer Research Institute-Irvington FellowshipUNSPECIFIED
Albert Billings Ruddock ProfessorshipUNSPECIFIED
Al Sherman FoundationUNSPECIFIED
Louis A. Garfinkle Memorial Laboratory FundUNSPECIFIED
PubMed Central ID:PMC3990665
Record Number:CaltechAUTHORS:20131028-142315690
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Official Citation:Transcriptional Establishment of Cell-Type Identity: Dynamics and Causal Mechanisms of T-Cell Lineage Commitment Ellen V. Rothenberg, Ameya Champhekar, Sagar Damle, Marissa Morales Del Real, Hao Yuan Kueh, Long Li, and Mary A. Yui Cold Spring Harb Symp Quant Biol doi:10.1101/sqb.2013.78.020271
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:42100
Deposited By: Ruth Sustaita
Deposited On:29 Oct 2013 14:41
Last Modified:10 Nov 2021 04:38

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