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Gata2 +9.5 enhancer regulates adult hematopoietic stem cell self-renewal and T-cell development

Mammalian GATA2 gene encodes a dual zinc finger transcription factor, which is essential for hematopoietic stem cell (HSC) generation in the aorta, gonad, mesonephros (AGM) region, HSC self-renewal, and specification of progenitor cell fates. Previously, we demonstrated that Gata2 expression in AGM...

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Autores principales: You, Xiaona, Zhou, Yun, Chang, Yuan-I, Kong, Guangyao, Ranheim, Erik A., Johnson, Kirby D., Soukup, Alexandra A., Bresnick, Emery H., Zhang, Jing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Hematology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8864660/
https://www.ncbi.nlm.nih.gov/pubmed/34516632
http://dx.doi.org/10.1182/bloodadvances.2021004311
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author You, Xiaona
Zhou, Yun
Chang, Yuan-I
Kong, Guangyao
Ranheim, Erik A.
Johnson, Kirby D.
Soukup, Alexandra A.
Bresnick, Emery H.
Zhang, Jing
author_facet You, Xiaona
Zhou, Yun
Chang, Yuan-I
Kong, Guangyao
Ranheim, Erik A.
Johnson, Kirby D.
Soukup, Alexandra A.
Bresnick, Emery H.
Zhang, Jing
author_sort You, Xiaona
collection PubMed
description Mammalian GATA2 gene encodes a dual zinc finger transcription factor, which is essential for hematopoietic stem cell (HSC) generation in the aorta, gonad, mesonephros (AGM) region, HSC self-renewal, and specification of progenitor cell fates. Previously, we demonstrated that Gata2 expression in AGM is controlled by its intronic +9.5 enhancer. Gata2 +9.5 deficiency removes the E-box motif and the GATA site and depletes fetal liver HSCs. However, whether this enhancer has an essential role in regulating adult hematopoiesis has not been established. Here, we evaluate Gata2 +9.5 enhancer function in adult hematopoiesis. +9.5(+/−) bone marrow cells displayed reduced T cell reconstitution in a competitive transplant assay. Donor-derived analysis demonstrated a previously unrecognized function of the +9.5 enhancer in T cell development at the lymphoid-primed multipotent progenitor stage. Moreover, +9.5(+/−) adult HSCs displayed increased apoptosis and reduced long-term self-renewal capability in comparison with wild-type (WT) HSCs. These phenotypes were more moderate than those of Gata2(+/−) HSCs. Consistent with the phenotypic characterization, Gata2 expression in +9.5(+/−) LSKs was moderately higher than that in Gata2(+/−) LSKs, but lower than that in WT LSKs. Our data suggest that +9.5 deficiency compromises, without completely abrogating, Gata2 expression in adult HSCs.
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spelling pubmed-88646602022-02-23 Gata2 +9.5 enhancer regulates adult hematopoietic stem cell self-renewal and T-cell development You, Xiaona Zhou, Yun Chang, Yuan-I Kong, Guangyao Ranheim, Erik A. Johnson, Kirby D. Soukup, Alexandra A. Bresnick, Emery H. Zhang, Jing Blood Adv Stimulus Report Mammalian GATA2 gene encodes a dual zinc finger transcription factor, which is essential for hematopoietic stem cell (HSC) generation in the aorta, gonad, mesonephros (AGM) region, HSC self-renewal, and specification of progenitor cell fates. Previously, we demonstrated that Gata2 expression in AGM is controlled by its intronic +9.5 enhancer. Gata2 +9.5 deficiency removes the E-box motif and the GATA site and depletes fetal liver HSCs. However, whether this enhancer has an essential role in regulating adult hematopoiesis has not been established. Here, we evaluate Gata2 +9.5 enhancer function in adult hematopoiesis. +9.5(+/−) bone marrow cells displayed reduced T cell reconstitution in a competitive transplant assay. Donor-derived analysis demonstrated a previously unrecognized function of the +9.5 enhancer in T cell development at the lymphoid-primed multipotent progenitor stage. Moreover, +9.5(+/−) adult HSCs displayed increased apoptosis and reduced long-term self-renewal capability in comparison with wild-type (WT) HSCs. These phenotypes were more moderate than those of Gata2(+/−) HSCs. Consistent with the phenotypic characterization, Gata2 expression in +9.5(+/−) LSKs was moderately higher than that in Gata2(+/−) LSKs, but lower than that in WT LSKs. Our data suggest that +9.5 deficiency compromises, without completely abrogating, Gata2 expression in adult HSCs. American Society of Hematology 2022-02-11 /pmc/articles/PMC8864660/ /pubmed/34516632 http://dx.doi.org/10.1182/bloodadvances.2021004311 Text en © 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
spellingShingle Stimulus Report
You, Xiaona
Zhou, Yun
Chang, Yuan-I
Kong, Guangyao
Ranheim, Erik A.
Johnson, Kirby D.
Soukup, Alexandra A.
Bresnick, Emery H.
Zhang, Jing
Gata2 +9.5 enhancer regulates adult hematopoietic stem cell self-renewal and T-cell development
title Gata2 +9.5 enhancer regulates adult hematopoietic stem cell self-renewal and T-cell development
title_full Gata2 +9.5 enhancer regulates adult hematopoietic stem cell self-renewal and T-cell development
title_fullStr Gata2 +9.5 enhancer regulates adult hematopoietic stem cell self-renewal and T-cell development
title_full_unstemmed Gata2 +9.5 enhancer regulates adult hematopoietic stem cell self-renewal and T-cell development
title_short Gata2 +9.5 enhancer regulates adult hematopoietic stem cell self-renewal and T-cell development
title_sort gata2 +9.5 enhancer regulates adult hematopoietic stem cell self-renewal and t-cell development
topic Stimulus Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8864660/
https://www.ncbi.nlm.nih.gov/pubmed/34516632
http://dx.doi.org/10.1182/bloodadvances.2021004311
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