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Stat and interferon genes identified by network analysis differentially regulate primitive and definitive erythropoiesis

BACKGROUND: Hematopoietic ontogeny is characterized by overlapping waves of primitive, fetal definitive, and adult definitive erythroid lineages. Our aim is to identify differences in the transcriptional control of these distinct erythroid cell maturation pathways by inferring and analyzing gene-int...

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Autores principales: Greenfest-Allen, Emily, Malik, Jeffrey, Palis, James, Stoeckert, Christian J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3668222/
https://www.ncbi.nlm.nih.gov/pubmed/23675896
http://dx.doi.org/10.1186/1752-0509-7-38
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author Greenfest-Allen, Emily
Malik, Jeffrey
Palis, James
Stoeckert, Christian J
author_facet Greenfest-Allen, Emily
Malik, Jeffrey
Palis, James
Stoeckert, Christian J
author_sort Greenfest-Allen, Emily
collection PubMed
description BACKGROUND: Hematopoietic ontogeny is characterized by overlapping waves of primitive, fetal definitive, and adult definitive erythroid lineages. Our aim is to identify differences in the transcriptional control of these distinct erythroid cell maturation pathways by inferring and analyzing gene-interaction networks from lineage-specific expression datasets. Inferred networks are strongly connected and do not fit a scale-free model, making it difficult to identify essential regulators using the hub-essentiality standard. RESULTS: We employed a semi-supervised machine learning approach to integrate measures of network topology with expression data to score gene essentiality. The algorithm was trained and tested on the adult and fetal definitive erythroid lineages. When applied to the primitive erythroid lineage, 144 high scoring transcription factors were found to be differentially expressed between the primitive and adult definitive erythroid lineages, including all expressed STAT-family members. Differential responses of primitive and definitive erythroblasts to a Stat3 inhibitor and IFNγ in vitro supported the results of the computational analysis. Further investigation of the original expression data revealed a striking signature of Stat1-related genes in the adult definitive erythroid network. Among the potential pathways known to utilize Stat1, interferon (IFN) signaling-related genes were expressed almost exclusively within the adult definitive erythroid network. CONCLUSIONS: In vitro results support the computational prediction that differential regulation and downstream effectors of STAT signaling are key factors that distinguish the transcriptional control of primitive and definitive erythroid cell maturation.
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spelling pubmed-36682222013-06-03 Stat and interferon genes identified by network analysis differentially regulate primitive and definitive erythropoiesis Greenfest-Allen, Emily Malik, Jeffrey Palis, James Stoeckert, Christian J BMC Syst Biol Research Article BACKGROUND: Hematopoietic ontogeny is characterized by overlapping waves of primitive, fetal definitive, and adult definitive erythroid lineages. Our aim is to identify differences in the transcriptional control of these distinct erythroid cell maturation pathways by inferring and analyzing gene-interaction networks from lineage-specific expression datasets. Inferred networks are strongly connected and do not fit a scale-free model, making it difficult to identify essential regulators using the hub-essentiality standard. RESULTS: We employed a semi-supervised machine learning approach to integrate measures of network topology with expression data to score gene essentiality. The algorithm was trained and tested on the adult and fetal definitive erythroid lineages. When applied to the primitive erythroid lineage, 144 high scoring transcription factors were found to be differentially expressed between the primitive and adult definitive erythroid lineages, including all expressed STAT-family members. Differential responses of primitive and definitive erythroblasts to a Stat3 inhibitor and IFNγ in vitro supported the results of the computational analysis. Further investigation of the original expression data revealed a striking signature of Stat1-related genes in the adult definitive erythroid network. Among the potential pathways known to utilize Stat1, interferon (IFN) signaling-related genes were expressed almost exclusively within the adult definitive erythroid network. CONCLUSIONS: In vitro results support the computational prediction that differential regulation and downstream effectors of STAT signaling are key factors that distinguish the transcriptional control of primitive and definitive erythroid cell maturation. BioMed Central 2013-05-15 /pmc/articles/PMC3668222/ /pubmed/23675896 http://dx.doi.org/10.1186/1752-0509-7-38 Text en Copyright © 2013 Greenfest-Allen et al.; 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.
spellingShingle Research Article
Greenfest-Allen, Emily
Malik, Jeffrey
Palis, James
Stoeckert, Christian J
Stat and interferon genes identified by network analysis differentially regulate primitive and definitive erythropoiesis
title Stat and interferon genes identified by network analysis differentially regulate primitive and definitive erythropoiesis
title_full Stat and interferon genes identified by network analysis differentially regulate primitive and definitive erythropoiesis
title_fullStr Stat and interferon genes identified by network analysis differentially regulate primitive and definitive erythropoiesis
title_full_unstemmed Stat and interferon genes identified by network analysis differentially regulate primitive and definitive erythropoiesis
title_short Stat and interferon genes identified by network analysis differentially regulate primitive and definitive erythropoiesis
title_sort stat and interferon genes identified by network analysis differentially regulate primitive and definitive erythropoiesis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3668222/
https://www.ncbi.nlm.nih.gov/pubmed/23675896
http://dx.doi.org/10.1186/1752-0509-7-38
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