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Multi-scale dynamical modelling of T-cell development from an early thymic progenitor state to lineage commitment

Olariu, Victor and Yui, Mary A. and Krupinski, Pawel and Zhou, Wen and Deichmann, Julia and Rothenberg, Ellen V. and Peterson, Carsten (2019) Multi-scale dynamical modelling of T-cell development from an early thymic progenitor state to lineage commitment. . (Unpublished) http://resolver.caltech.edu/CaltechAUTHORS:20190612-072821066

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Abstract

Thymic development of committed pro-T-cells from multipotent hematopoietic precursors offers a unique opportunity to dissect the molecular circuitry establishing cell identity in response to environmental signals. This transition encompasses programmed shutoff of stem/progenitor genes, upregulation of T-cell specification genes, extensive proliferation, and commitment after a delay. We have incorporated these factors, as well as new single cell gene expression and developmental kinetics data, into a three-level dynamic model of commitment based upon regulation of the commitment gene Bcl11b. The first level is a core gene regulatory network architecture determined by transcription factor perturbation data, the second a stochastically controlled epigenetic gate, and the third a proliferation model validated by growth and commitment kinetics measured at single-cell levels. Using expression values consistent with single molecule RNA-FISH measurements of key transcription factors, this single-cell model exhibits state switching consistent with measured population and clonal proliferation and commitment times. The resulting multi-scale model provides a powerful mechanistic framework for dissecting commitment dynamics.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/667709DOIDiscussion Paper
ORCID:
AuthorORCID
Yui, Mary A.0000-0002-3136-2181
Rothenberg, Ellen V.0000-0002-3901-347X
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. bioRxiv preprint first posted online Jun. 11, 2019. The authors thank Dr. Long Cai for support for the smFISH analysis; Dr. Jeffrey Longmate for data analysis; Dr. Hao Yuan Kueh for helpful discussions and advice on imaging and analysis; Kenneth Ng for technical help; Diana Perez, Jamie Tijerina, and Rochelle Diamond of the Caltech Flow Cytometry Facility for FACS cell sorting; Dr. Andreas Collazo and the Caltech Biological Imaging Facility for microscopy assistance. The authors gratefully acknowledge the support of the US National Institutes of Health (USPHS grant R01HL119102 to E.V.R. and C.P.) and the Albert Billings Ruddock Professorship (to E.V.R). Author Contributions: VO, MY, EVR and CP designed the study. VO, MY, EVR and CP wrote most of the manuscript. MY performed the CTV and kinetics experiments. WZ performed the FISH experiments. VO developed the transcriptional and epigenetic models and analyzed the data. PK developed the population model. JD implemented the pseudo time series and multi-scale models. The authors declare no competing interests.
Funders:
Funding AgencyGrant Number
NIHR01HL119102
Albert Billings Ruddock ProfessorshipUNSPECIFIED
Record Number:CaltechAUTHORS:20190612-072821066
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20190612-072821066
Official Citation:Multi-scale dynamical modelling of T-cell development from an early thymic progenitor state to lineage commitment. Victor Olariu, Mary Yui, Pawel Krupinski, Wen Zhou, Julia Deichmann, Ellen V Rothenberg, Carsten Peterson. bioRxiv 667709; doi: https://doi.org/10.1101/667709
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:96306
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:12 Jun 2019 15:15
Last Modified:12 Jun 2019 15:15

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