PMID- 33440162
OWN - NLM
STAT- MEDLINE
DCOM- 20220104
LR  - 20220104
IS  - 2211-1247 (Electronic)
VI  - 34
IP  - 2
DP  - 2021 Jan 12
TI  - Multi-scale Dynamical Modeling of T Cell Development from an Early Thymic 
      Progenitor State to Lineage Commitment.
PG  - 108622
LID - S2211-1247(20)31611-9 [pii]
LID - 10.1016/j.celrep.2020.108622 [doi]
AB  - Intrathymic development of committed progenitor (pro)-T cells from multipotent 
      hematopoietic precursors offers an 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, proliferation, and ultimately commitment. To explain these 
      features in light of reported cis-acting chromatin effects and experimental 
      kinetic data, we develop a three-level dynamic model of commitment based upon 
      regulation of the commitment-linked gene Bcl11b. The levels are (1) a core gene 
      regulatory network (GRN) architecture from transcription factor (TF) perturbation 
      data, (2) a stochastically controlled chromatin-state gate, and (3) a single-cell 
      proliferation model validated by experimental clonal growth and commitment 
      kinetic assays. Using RNA fluorescence in situ hybridization (FISH) measurements 
      of genes encoding key TFs and measured bulk population dynamics, this single-cell 
      model predicts state-switching kinetics validated by measured clonal 
      proliferation and commitment times. The resulting multi-scale model provides a 
      mechanistic framework for dissecting commitment dynamics.
CI  - Copyright (c) 2020. Published by Elsevier Inc.
FAU - Olariu, Victor
AU  - Olariu V
AD  - Computational Biology and Biological Physics, Department of Astronomy and 
      Theoretical Physics, Lund University, Lund, Sweden.
FAU - Yui, Mary A
AU  - Yui MA
AD  - Division of Biology and Biological Engineering, 156-29, California Institute of 
      Technology, Pasadena, CA 91125, USA.
FAU - Krupinski, Pawel
AU  - Krupinski P
AD  - Computational Biology and Biological Physics, Department of Astronomy and 
      Theoretical Physics, Lund University, Lund, Sweden.
FAU - Zhou, Wen
AU  - Zhou W
AD  - Division of Biology and Biological Engineering, 156-29, California Institute of 
      Technology, Pasadena, CA 91125, USA.
FAU - Deichmann, Julia
AU  - Deichmann J
AD  - Computational Biology and Biological Physics, Department of Astronomy and 
      Theoretical Physics, Lund University, Lund, Sweden.
FAU - Andersson, Emil
AU  - Andersson E
AD  - Computational Biology and Biological Physics, Department of Astronomy and 
      Theoretical Physics, Lund University, Lund, Sweden.
FAU - Rothenberg, Ellen V
AU  - Rothenberg EV
AD  - Division of Biology and Biological Engineering, 156-29, California Institute of 
      Technology, Pasadena, CA 91125, USA. Electronic address: evroth@its.caltech.edu.
FAU - Peterson, Carsten
AU  - Peterson C
AD  - Computational Biology and Biological Physics, Department of Astronomy and 
      Theoretical Physics, Lund University, Lund, Sweden. Electronic address: 
      carsten@thep.lu.se.
LA  - eng
GR  - R01 HL119102/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cell Rep
JT  - Cell reports
JID - 101573691
SB  - IM
MH  - Cell Differentiation
MH  - Cell Lineage/*genetics
MH  - Humans
MH  - Stem Cells/*metabolism
MH  - T-Lymphocytes/*physiology
MH  - Thymus Gland/*metabolism
PMC - PMC7943435
MID - NIHMS1670076
OTO - NOTNLM
OT  - T cell development
OT  - epigenetic modeling
OT  - experimental validations
OT  - kinetic measurements
OT  - population modeling
OT  - proliferation measurements
OT  - single-cell measurements
OT  - stochastic simulations
OT  - transcriptional modeling
COIS- Declaration of Interests The authors declare no competing interests.
EDAT- 2021/01/14 06:00
MHDA- 2022/01/05 06:00
PMCR- 2021/03/10
CRDT- 2021/01/13 20:06
PHST- 2019/10/15 00:00 [received]
PHST- 2020/04/24 00:00 [revised]
PHST- 2020/12/18 00:00 [accepted]
PHST- 2021/01/13 20:06 [entrez]
PHST- 2021/01/14 06:00 [pubmed]
PHST- 2022/01/05 06:00 [medline]
PHST- 2021/03/10 00:00 [pmc-release]
AID - S2211-1247(20)31611-9 [pii]
AID - 10.1016/j.celrep.2020.108622 [doi]
PST - ppublish
SO  - Cell Rep. 2021 Jan 12;34(2):108622. doi: 10.1016/j.celrep.2020.108622.