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Mathematical modeling of GATA-switching for regulating the differentiation of hematopoietic stem cell

BACKGROUND: Hematopoiesis is a highly orchestrated developmental process that comprises various developmental stages of the hematopoietic stem cells (HSCs). During development, the decision to leave the self-renewing state and selection of a differentiation pathway is regulated by a number of transc...

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Autores principales: Tian, Tianhai, Smith-Miles, Kate
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4080254/
https://www.ncbi.nlm.nih.gov/pubmed/24565335
http://dx.doi.org/10.1186/1752-0509-8-S1-S8
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author Tian, Tianhai
Smith-Miles, Kate
author_facet Tian, Tianhai
Smith-Miles, Kate
author_sort Tian, Tianhai
collection PubMed
description BACKGROUND: Hematopoiesis is a highly orchestrated developmental process that comprises various developmental stages of the hematopoietic stem cells (HSCs). During development, the decision to leave the self-renewing state and selection of a differentiation pathway is regulated by a number of transcription factors. Among them, genes GATA-1 and PU.1 form a core negative feedback module to regulate the genetic switching between the cell fate choices of HSCs. Although extensive experimental studies have revealed the mechanisms to regulate the expression of these two genes, it is still unclear how this simple module regulates the genetic switching. METHODS: In this work we proposed a mathematical model to study the mechanisms of the GATA-PU.1 gene network in the determination of HSC differentiation pathways. We incorporated the mechanisms of GATA switch into the module, and developed a mathematical model that comprises three genes GATA-1, GATA-2 and PU.1. In addition, a novel multiple-objective optimization method was designed to infer unknown parameters in the proposed model by realizing different experimental observations. A stochastic model was also designed to describe the critical function of noise, due to the small copy numbers of molecular species, in determining the differentiation pathways. RESULTS: The proposed deterministic model has successfully realized three stable steady states representing the priming and different progenitor cells as well as genetic switching between the genetic states under various experimental conditions. Using different values of GATA-1 synthesis rate for the GATA-1 protein availability in the chromatin sites during the time period of GATA switch, stochastic simulations for the first time have realized different proportions of cells leading to different developmental pathways under various experimental conditions. CONCLUSIONS: Mathematical models provide testable predictions regarding the mechanisms and conditions for realizing different differentiation pathways of hematopoietic stem cells. This work represents the first attempt at using a discrete stochastic model to realize the decision of HSC differentiation pathways showing a multimodal distribution.
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spelling pubmed-40802542014-07-14 Mathematical modeling of GATA-switching for regulating the differentiation of hematopoietic stem cell Tian, Tianhai Smith-Miles, Kate BMC Syst Biol Proceedings BACKGROUND: Hematopoiesis is a highly orchestrated developmental process that comprises various developmental stages of the hematopoietic stem cells (HSCs). During development, the decision to leave the self-renewing state and selection of a differentiation pathway is regulated by a number of transcription factors. Among them, genes GATA-1 and PU.1 form a core negative feedback module to regulate the genetic switching between the cell fate choices of HSCs. Although extensive experimental studies have revealed the mechanisms to regulate the expression of these two genes, it is still unclear how this simple module regulates the genetic switching. METHODS: In this work we proposed a mathematical model to study the mechanisms of the GATA-PU.1 gene network in the determination of HSC differentiation pathways. We incorporated the mechanisms of GATA switch into the module, and developed a mathematical model that comprises three genes GATA-1, GATA-2 and PU.1. In addition, a novel multiple-objective optimization method was designed to infer unknown parameters in the proposed model by realizing different experimental observations. A stochastic model was also designed to describe the critical function of noise, due to the small copy numbers of molecular species, in determining the differentiation pathways. RESULTS: The proposed deterministic model has successfully realized three stable steady states representing the priming and different progenitor cells as well as genetic switching between the genetic states under various experimental conditions. Using different values of GATA-1 synthesis rate for the GATA-1 protein availability in the chromatin sites during the time period of GATA switch, stochastic simulations for the first time have realized different proportions of cells leading to different developmental pathways under various experimental conditions. CONCLUSIONS: Mathematical models provide testable predictions regarding the mechanisms and conditions for realizing different differentiation pathways of hematopoietic stem cells. This work represents the first attempt at using a discrete stochastic model to realize the decision of HSC differentiation pathways showing a multimodal distribution. BioMed Central 2014-01-24 /pmc/articles/PMC4080254/ /pubmed/24565335 http://dx.doi.org/10.1186/1752-0509-8-S1-S8 Text en Copyright © 2014 Tian and Smith-Miles; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Proceedings
Tian, Tianhai
Smith-Miles, Kate
Mathematical modeling of GATA-switching for regulating the differentiation of hematopoietic stem cell
title Mathematical modeling of GATA-switching for regulating the differentiation of hematopoietic stem cell
title_full Mathematical modeling of GATA-switching for regulating the differentiation of hematopoietic stem cell
title_fullStr Mathematical modeling of GATA-switching for regulating the differentiation of hematopoietic stem cell
title_full_unstemmed Mathematical modeling of GATA-switching for regulating the differentiation of hematopoietic stem cell
title_short Mathematical modeling of GATA-switching for regulating the differentiation of hematopoietic stem cell
title_sort mathematical modeling of gata-switching for regulating the differentiation of hematopoietic stem cell
topic Proceedings
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4080254/
https://www.ncbi.nlm.nih.gov/pubmed/24565335
http://dx.doi.org/10.1186/1752-0509-8-S1-S8
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