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CCCTC-binding factor is essential to the maintenance and quiescence of hematopoietic stem cells in mice
Hematopoiesis involves a series of lineage differentiation programs initiated in hematopoietic stem cells (HSCs) found in bone marrow (BM). To ensure lifelong hematopoiesis, various molecular mechanisms are needed to maintain the HSC pool. CCCTC-binding factor (CTCF) is a DNA-binding, zinc-finger pr...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5579513/ https://www.ncbi.nlm.nih.gov/pubmed/28857086 http://dx.doi.org/10.1038/emm.2017.124 |
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author | Kim, Tae-Gyun Kim, Sueun Jung, Soyeon Kim, Mikyoung Yang, Bobae Lee, Min-Geol Kim, Hyoung-Pyo |
author_facet | Kim, Tae-Gyun Kim, Sueun Jung, Soyeon Kim, Mikyoung Yang, Bobae Lee, Min-Geol Kim, Hyoung-Pyo |
author_sort | Kim, Tae-Gyun |
collection | PubMed |
description | Hematopoiesis involves a series of lineage differentiation programs initiated in hematopoietic stem cells (HSCs) found in bone marrow (BM). To ensure lifelong hematopoiesis, various molecular mechanisms are needed to maintain the HSC pool. CCCTC-binding factor (CTCF) is a DNA-binding, zinc-finger protein that regulates the expression of its target gene by organizing higher order chromatin structures. Currently, the role of CTCF in controlling HSC homeostasis is unknown. Using a tamoxifen-inducible CTCF conditional knockout mouse system, we aimed to determine whether CTCF regulates the homeostatic maintenance of HSCs. In adult mice, acute systemic CTCF ablation led to severe BM failure and the rapid shrinkage of multiple c-Kit(hi) progenitor populations, including Sca-1(+) HSCs. Similarly, hematopoietic system-confined CTCF depletion caused an acute loss of HSCs and highly increased mortality. Mixed BM chimeras reconstituted with supporting BM demonstrated that CTCF deficiency-mediated HSC depletion has both cell-extrinsic and cell-intrinsic effects. Although c-Kit(hi) myeloid progenitor cell populations were severely reduced after ablating Ctcf, c-Kit(int) common lymphoid progenitors and their progenies were less affected by the lack of CTCF. Whole-transcriptome microarray and cell cycle analyses indicated that CTCF deficiency results in the enhanced expression of the cell cycle-promoting program, and that CTCF-depleted HSCs express higher levels of reactive oxygen species (ROS). Importantly, in vivo treatment with an antioxidant partially rescued c-Kit(hi) cell populations and their quiescence. Altogether, our results suggest that CTCF is indispensable for maintaining adult HSC pools, likely by regulating ROS-dependent HSC quiescence. |
format | Online Article Text |
id | pubmed-5579513 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-55795132017-09-15 CCCTC-binding factor is essential to the maintenance and quiescence of hematopoietic stem cells in mice Kim, Tae-Gyun Kim, Sueun Jung, Soyeon Kim, Mikyoung Yang, Bobae Lee, Min-Geol Kim, Hyoung-Pyo Exp Mol Med Original Article Hematopoiesis involves a series of lineage differentiation programs initiated in hematopoietic stem cells (HSCs) found in bone marrow (BM). To ensure lifelong hematopoiesis, various molecular mechanisms are needed to maintain the HSC pool. CCCTC-binding factor (CTCF) is a DNA-binding, zinc-finger protein that regulates the expression of its target gene by organizing higher order chromatin structures. Currently, the role of CTCF in controlling HSC homeostasis is unknown. Using a tamoxifen-inducible CTCF conditional knockout mouse system, we aimed to determine whether CTCF regulates the homeostatic maintenance of HSCs. In adult mice, acute systemic CTCF ablation led to severe BM failure and the rapid shrinkage of multiple c-Kit(hi) progenitor populations, including Sca-1(+) HSCs. Similarly, hematopoietic system-confined CTCF depletion caused an acute loss of HSCs and highly increased mortality. Mixed BM chimeras reconstituted with supporting BM demonstrated that CTCF deficiency-mediated HSC depletion has both cell-extrinsic and cell-intrinsic effects. Although c-Kit(hi) myeloid progenitor cell populations were severely reduced after ablating Ctcf, c-Kit(int) common lymphoid progenitors and their progenies were less affected by the lack of CTCF. Whole-transcriptome microarray and cell cycle analyses indicated that CTCF deficiency results in the enhanced expression of the cell cycle-promoting program, and that CTCF-depleted HSCs express higher levels of reactive oxygen species (ROS). Importantly, in vivo treatment with an antioxidant partially rescued c-Kit(hi) cell populations and their quiescence. Altogether, our results suggest that CTCF is indispensable for maintaining adult HSC pools, likely by regulating ROS-dependent HSC quiescence. Nature Publishing Group 2017-08 2017-08-25 /pmc/articles/PMC5579513/ /pubmed/28857086 http://dx.doi.org/10.1038/emm.2017.124 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ |
spellingShingle | Original Article Kim, Tae-Gyun Kim, Sueun Jung, Soyeon Kim, Mikyoung Yang, Bobae Lee, Min-Geol Kim, Hyoung-Pyo CCCTC-binding factor is essential to the maintenance and quiescence of hematopoietic stem cells in mice |
title | CCCTC-binding factor is essential to the maintenance and quiescence of hematopoietic stem cells in mice |
title_full | CCCTC-binding factor is essential to the maintenance and quiescence of hematopoietic stem cells in mice |
title_fullStr | CCCTC-binding factor is essential to the maintenance and quiescence of hematopoietic stem cells in mice |
title_full_unstemmed | CCCTC-binding factor is essential to the maintenance and quiescence of hematopoietic stem cells in mice |
title_short | CCCTC-binding factor is essential to the maintenance and quiescence of hematopoietic stem cells in mice |
title_sort | ccctc-binding factor is essential to the maintenance and quiescence of hematopoietic stem cells in mice |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5579513/ https://www.ncbi.nlm.nih.gov/pubmed/28857086 http://dx.doi.org/10.1038/emm.2017.124 |
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