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BAF180 regulates cellular senescence and hematopoietic stem cell homeostasis through p21

BAF180 (also called PBRM1), a subunit of the SWI/SNF complex, plays critical roles in the regulation of chromatin remodeling and gene transcription, and is frequently mutated in several human cancers. However, the role of mammalian BAF180 in tumor suppression and tissue maintenance in vivo remains l...

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Autores principales: Lee, Hyemin, Dai, Fangyan, Zhuang, Li, Xiao, Zhen-Dong, Kim, Jongchan, Zhang, Yilei, Ma, Li, You, M. James, Wang, Zhong, Gan, Boyi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991371/
https://www.ncbi.nlm.nih.gov/pubmed/26992241
http://dx.doi.org/10.18632/oncotarget.8102
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author Lee, Hyemin
Dai, Fangyan
Zhuang, Li
Xiao, Zhen-Dong
Kim, Jongchan
Zhang, Yilei
Ma, Li
You, M. James
Wang, Zhong
Gan, Boyi
author_facet Lee, Hyemin
Dai, Fangyan
Zhuang, Li
Xiao, Zhen-Dong
Kim, Jongchan
Zhang, Yilei
Ma, Li
You, M. James
Wang, Zhong
Gan, Boyi
author_sort Lee, Hyemin
collection PubMed
description BAF180 (also called PBRM1), a subunit of the SWI/SNF complex, plays critical roles in the regulation of chromatin remodeling and gene transcription, and is frequently mutated in several human cancers. However, the role of mammalian BAF180 in tumor suppression and tissue maintenance in vivo remains largely unknown. Here, using a conditional somatic knockout approach, we explored the cellular and organismal functions of BAF180 in mouse. BAF180 deletion in primary mouse embryonic fibroblasts (MEFs) triggers profound cell cycle arrest, premature cellular senescence, without affecting DNA damage response or chromosomal integrity. While somatic deletion of BAF180 in adult mice does not provoke tumor development, BAF180 deficient mice exhibit defects in hematopoietic system characterized by progressive reduction of hematopoietic stem cells (HSCs), defective long-term repopulating potential, and hematopoietic lineage developmental aberrations. BAF180 deletion results in elevated p21 expression in both MEFs and HSCs. Mechanistically, we showed that BAF180 binds to p21 promoter, and BAF180 deletion enhances the binding of modified histones associated with transcriptional activation on p21 promoter. Deletion of p21 rescues cell cycle arrest and premature senescence in BAF180 deficient MEFs, and partially rescues hematopoietic defects in BAF180 deficient mice. Together, our study identifies BAF180 as a critical regulator of cellular senescence and HSC homeostasis, which is at least partially regulated through BAF180-mediated suppression of p21 expression. Our results also suggest that senescence triggered by BAF180 inactivation may serve as a failsafe mechanism to restrain BAF180 deficiency-associated tumor development, providing a conceptual framework to further understand BAF180 function in tumor biology.
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spelling pubmed-49913712016-09-01 BAF180 regulates cellular senescence and hematopoietic stem cell homeostasis through p21 Lee, Hyemin Dai, Fangyan Zhuang, Li Xiao, Zhen-Dong Kim, Jongchan Zhang, Yilei Ma, Li You, M. James Wang, Zhong Gan, Boyi Oncotarget Research Paper: Gerotarget (Focus on Aging) BAF180 (also called PBRM1), a subunit of the SWI/SNF complex, plays critical roles in the regulation of chromatin remodeling and gene transcription, and is frequently mutated in several human cancers. However, the role of mammalian BAF180 in tumor suppression and tissue maintenance in vivo remains largely unknown. Here, using a conditional somatic knockout approach, we explored the cellular and organismal functions of BAF180 in mouse. BAF180 deletion in primary mouse embryonic fibroblasts (MEFs) triggers profound cell cycle arrest, premature cellular senescence, without affecting DNA damage response or chromosomal integrity. While somatic deletion of BAF180 in adult mice does not provoke tumor development, BAF180 deficient mice exhibit defects in hematopoietic system characterized by progressive reduction of hematopoietic stem cells (HSCs), defective long-term repopulating potential, and hematopoietic lineage developmental aberrations. BAF180 deletion results in elevated p21 expression in both MEFs and HSCs. Mechanistically, we showed that BAF180 binds to p21 promoter, and BAF180 deletion enhances the binding of modified histones associated with transcriptional activation on p21 promoter. Deletion of p21 rescues cell cycle arrest and premature senescence in BAF180 deficient MEFs, and partially rescues hematopoietic defects in BAF180 deficient mice. Together, our study identifies BAF180 as a critical regulator of cellular senescence and HSC homeostasis, which is at least partially regulated through BAF180-mediated suppression of p21 expression. Our results also suggest that senescence triggered by BAF180 inactivation may serve as a failsafe mechanism to restrain BAF180 deficiency-associated tumor development, providing a conceptual framework to further understand BAF180 function in tumor biology. Impact Journals LLC 2016-03-15 /pmc/articles/PMC4991371/ /pubmed/26992241 http://dx.doi.org/10.18632/oncotarget.8102 Text en Copyright: © 2016 Lee et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper: Gerotarget (Focus on Aging)
Lee, Hyemin
Dai, Fangyan
Zhuang, Li
Xiao, Zhen-Dong
Kim, Jongchan
Zhang, Yilei
Ma, Li
You, M. James
Wang, Zhong
Gan, Boyi
BAF180 regulates cellular senescence and hematopoietic stem cell homeostasis through p21
title BAF180 regulates cellular senescence and hematopoietic stem cell homeostasis through p21
title_full BAF180 regulates cellular senescence and hematopoietic stem cell homeostasis through p21
title_fullStr BAF180 regulates cellular senescence and hematopoietic stem cell homeostasis through p21
title_full_unstemmed BAF180 regulates cellular senescence and hematopoietic stem cell homeostasis through p21
title_short BAF180 regulates cellular senescence and hematopoietic stem cell homeostasis through p21
title_sort baf180 regulates cellular senescence and hematopoietic stem cell homeostasis through p21
topic Research Paper: Gerotarget (Focus on Aging)
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991371/
https://www.ncbi.nlm.nih.gov/pubmed/26992241
http://dx.doi.org/10.18632/oncotarget.8102
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