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Preprint
A stochastic epigenetic switch controls the dynamics of T-cell lineage commitment
biorxiv.org
10 May 2018
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
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Details
- Title
- A stochastic epigenetic switch controls the dynamics of T-cell lineage commitment
- Creators
- Kenneth Kh Ng - University of WashingtonMary A Yui - California Institute of TechnologyArnav Mehta - California Institute of TechnologySharmayne Siu - Drexel University, Philadelphia, United StatesBlythe Irwin - University of WashingtonShirley Pease - California Institute of TechnologySatoshi Hirose - California Institute of TechnologyMichael B Elowitz - California Institute of TechnologyEllen V Rothenberg - California Institute of TechnologyHao Yuan Kueh - University of Washington
- Publication Details
- biorxiv.org
- Publisher
- American Physical Society (APS)
- Grant note
- R00HL119638 / NIH HHS R01HL119102 / NIH HHS R00 HL119638 / NHLBI NIH HHS R01 AI095943 / NIAID NIH HHS R01 AI083514 / NIAID NIH HHS Investigator / Howard Hughes Medical Institute R01AI083514 / NIH HHS R01 HL119102 / NHLBI NIH HHS R01AI095943 / NIH HHS
- Resource Type
- Preprint
- Language
- English
- Academic Unit
- Biology
- Web of Science ID
- WOS:000450547600001
- Other Identifier
- 991021883814204721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biology