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A stochastic epigenetic switch controls the dynamics of T-cell lineage commitment

Ng, Kenneth K. N. and Yui, Mary A. and Mehta, Arnav and Siu, Sharmayne and Irwin, Blythe and Pease, Shirley and Hirose, Satoshi and Elowitz, Michael B. and Rothenberg, Ellen V. and Kueh, Hao Yuan (2018) A stochastic epigenetic switch controls the dynamics of T-cell lineage commitment. eLife, 7 . Art. No. e37851. ISSN 2050-084X. PMCID PMC6245732.

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Cell fate decisions occur through the switch-like, irreversible activation of fate-specifying genes. These activation events are often assumed to be tightly coupled to changes in upstream transcription factors, but could also be constrained by cis-epigenetic mechanisms at individual gene loci. Here, we studied the activation of Bcl11b, which controls T-cell fate commitment. To disentangle cis and trans effects, we generated mice where two Bcl11b copies are tagged with distinguishable fluorescent proteins. Quantitative live microscopy of progenitors from these mice revealed that Bcl11b turned on after a stochastic delay averaging multiple days, which varied not only between cells but also between Bcl11b alleles within the same cell. Genetic perturbations, together with mathematical modeling, showed that a distal enhancer controls the rate of epigenetic activation, while a parallel Notch-dependent trans-acting step stimulates expression from activated loci. These results show that developmental fate transitions can be controlled by stochastic cis-acting events on individual loci.

Item Type:Article
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URLURL TypeDescription Paper CentralArticle
Yui, Mary A.0000-0002-3136-2181
Elowitz, Michael B.0000-0002-1221-0967
Rothenberg, Ellen V.0000-0002-3901-347X
Kueh, Hao Yuan0000-0001-6272-6673
Additional Information:© 2018 Ng et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Received: 26 April 2018; Accepted: 11 October 2018; Published: 20 November 2018. Data availability: Imaging data, along with MATLAB image processing scripts have been deposited in github: (copy archived at Source data for Figs. 2,3,4,5, Figure 3-figure supplements 1,2 and 3 have also been included. We thank M Lerica Gutierrez Quiloan for mouse genotyping and maintenance; N Verduzco and I Soto for animal husbandry; RA Diamond, K Beadle, and D Perez for cell sorting. We also thank members of Kueh, Rothenberg and Elowitz labs for feedback, and T Mitchison for valuable discussions. We also thank Sandy Nandagopal, Pulin Li, Zeba Wunderlich and Nick Pease for comments. This work was funded by an NIH K99/R00 Award (5R00HL119638), a Tietze Foundation Stem Cell Scientist Award, and a CRI/Irvington Postdoctoral Fellowship (to HYK); NIH grants R01AI095943, R01AI083514, and R01HL119102 (to EVR), California Institute for Regenerative Medicine Bridges to Stem Cell Research (to KKHN); and the Louis A Garfinkle Memorial Laboratory Fund, the Al Sherman Foundation, and the Albert Billings Ruddock Professorship (to EVR). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Ethics: Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Animals were bred and maintained in either the Laboratory Animal Facility of the California Institute of Technology, or that of the University of Washington. Animal protocols were reviewed and approved by the Institute Animal Care and Use Committees (IACUC) of the California Institute of Technology (Protocols #1445 and #1409) and the University of Washington Protocol #4397-01. Author contributions: Kenneth KH Ng, Data curation, Formal analysis, Investigation, Writing—original draft, Writing— review and editing; Mary A Yui, Data curation, Formal analysis, Investigation; Arnav Mehta, Satoshi Hirose, Investigation; Sharmayne Siu, Blythe Irwin, Formal analysis, Investigation; Shirley Pease, Resources; Michael B Elowitz, Ellen V Rothenberg, Conceptualization, Supervision, Funding acquisition, Methodology, Writing—original draft, Writing—review and editing; Hao Yuan Kueh, Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Investigation, Methodology, Writing—original draft, Writing—review and editing.
Funding AgencyGrant Number
Cancer Research InstituteUNSPECIFIED
California Institute for Regenerative Medicine (CIRM)UNSPECIFIED
Louis A. Garfinkle Memorial Laboratory FundUNSPECIFIED
Al Sherman FoundationUNSPECIFIED
Albert Billings Ruddock ProfessorshipUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
John H. Tietze Foundation TrustUNSPECIFIED
PubMed Central ID:PMC6245732
Record Number:CaltechAUTHORS:20181030-143317624
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:90521
Deposited By: Tony Diaz
Deposited On:30 Oct 2018 22:38
Last Modified:03 Oct 2019 20:26

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