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BMI1 fine-tunes gene repression and activation to safeguard undifferentiated spermatogonia fate
Introduction: Spermatogenesis is sustained by the homeostasis of self-renewal and differentiation of undifferentiated spermatogonia throughout life, which is regulated by transcriptional and posttranscriptional mechanisms. B cell-specific Moloney murine leukemia virus integration site 1 (BMI1), one...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10164956/ https://www.ncbi.nlm.nih.gov/pubmed/37169021 http://dx.doi.org/10.3389/fcell.2023.1146849 |
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author | Liu, Ruiqi Peng, Yonglin Du, Wenfei Wu, Yunqiang Zhang, Wen Hu, Congxia Liu, Min Liu, Xinhua Wu, Ji Sun, Jielin Zhao, Xiaodong |
author_facet | Liu, Ruiqi Peng, Yonglin Du, Wenfei Wu, Yunqiang Zhang, Wen Hu, Congxia Liu, Min Liu, Xinhua Wu, Ji Sun, Jielin Zhao, Xiaodong |
author_sort | Liu, Ruiqi |
collection | PubMed |
description | Introduction: Spermatogenesis is sustained by the homeostasis of self-renewal and differentiation of undifferentiated spermatogonia throughout life, which is regulated by transcriptional and posttranscriptional mechanisms. B cell-specific Moloney murine leukemia virus integration site 1 (BMI1), one of spermatogonial stem cell markers, is a member of Polycomb repressive complex 1 (PRC1) and important to spermatogenesis. However, the mechanistic underpinnings of how BMI1 regulates spermatogonia fate remain elusive. Methods: We knocked down BMI1 by siRNA to investigate the role of BMI1 in undifferentiated spermatogonia. Differentially expressed genes were identified by RNA-seq and used for KEGG pathway analysis. We performed ChIP-seq analysis in wild type and BMI1 knockdown cells to explore the underlying molecular mechanisms exerted by BMI1. BMI1-associated alterations in repressive histone modifications were detected via Western blotting and ChIP-seq. Furthermore, we performed mass spectrometry and Co-immunoprecipitation assays to investigate BMI1 co-factors. Finally, we demonstrated the genomic regions occupied by both BMI1 and its co-factor. Results: BMI1 is required for undifferentiated spermatogonia maintenance by both repressing and activating target genes. BMI1 preserves PI3K-Akt signaling pathway for spermatogonia proliferation. Decrease of BMI1 affects the deposition of repressive histone modifications H2AK119ub1 and H3K27me3. BMI also positively regulates H3K27ac deposited genes which are associated with proliferation. Moreover, we demonstrate that BMI1 interacts with Sal-like 4 (SALL4), the transcription factor critical for spermatogonia function, to co-regulate gene expression. Discussion: Overall, our study reveals that BMI1 safeguards undifferentiated spermatogonia fate through multi-functional roles in regulating gene expression programs of undifferentiated spermatogonia. |
format | Online Article Text |
id | pubmed-10164956 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-101649562023-05-09 BMI1 fine-tunes gene repression and activation to safeguard undifferentiated spermatogonia fate Liu, Ruiqi Peng, Yonglin Du, Wenfei Wu, Yunqiang Zhang, Wen Hu, Congxia Liu, Min Liu, Xinhua Wu, Ji Sun, Jielin Zhao, Xiaodong Front Cell Dev Biol Cell and Developmental Biology Introduction: Spermatogenesis is sustained by the homeostasis of self-renewal and differentiation of undifferentiated spermatogonia throughout life, which is regulated by transcriptional and posttranscriptional mechanisms. B cell-specific Moloney murine leukemia virus integration site 1 (BMI1), one of spermatogonial stem cell markers, is a member of Polycomb repressive complex 1 (PRC1) and important to spermatogenesis. However, the mechanistic underpinnings of how BMI1 regulates spermatogonia fate remain elusive. Methods: We knocked down BMI1 by siRNA to investigate the role of BMI1 in undifferentiated spermatogonia. Differentially expressed genes were identified by RNA-seq and used for KEGG pathway analysis. We performed ChIP-seq analysis in wild type and BMI1 knockdown cells to explore the underlying molecular mechanisms exerted by BMI1. BMI1-associated alterations in repressive histone modifications were detected via Western blotting and ChIP-seq. Furthermore, we performed mass spectrometry and Co-immunoprecipitation assays to investigate BMI1 co-factors. Finally, we demonstrated the genomic regions occupied by both BMI1 and its co-factor. Results: BMI1 is required for undifferentiated spermatogonia maintenance by both repressing and activating target genes. BMI1 preserves PI3K-Akt signaling pathway for spermatogonia proliferation. Decrease of BMI1 affects the deposition of repressive histone modifications H2AK119ub1 and H3K27me3. BMI also positively regulates H3K27ac deposited genes which are associated with proliferation. Moreover, we demonstrate that BMI1 interacts with Sal-like 4 (SALL4), the transcription factor critical for spermatogonia function, to co-regulate gene expression. Discussion: Overall, our study reveals that BMI1 safeguards undifferentiated spermatogonia fate through multi-functional roles in regulating gene expression programs of undifferentiated spermatogonia. Frontiers Media S.A. 2023-04-24 /pmc/articles/PMC10164956/ /pubmed/37169021 http://dx.doi.org/10.3389/fcell.2023.1146849 Text en Copyright © 2023 Liu, Peng, Du, Wu, Zhang, Hu, Liu, Liu, Wu, Sun and Zhao. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cell and Developmental Biology Liu, Ruiqi Peng, Yonglin Du, Wenfei Wu, Yunqiang Zhang, Wen Hu, Congxia Liu, Min Liu, Xinhua Wu, Ji Sun, Jielin Zhao, Xiaodong BMI1 fine-tunes gene repression and activation to safeguard undifferentiated spermatogonia fate |
title | BMI1 fine-tunes gene repression and activation to safeguard undifferentiated spermatogonia fate |
title_full | BMI1 fine-tunes gene repression and activation to safeguard undifferentiated spermatogonia fate |
title_fullStr | BMI1 fine-tunes gene repression and activation to safeguard undifferentiated spermatogonia fate |
title_full_unstemmed | BMI1 fine-tunes gene repression and activation to safeguard undifferentiated spermatogonia fate |
title_short | BMI1 fine-tunes gene repression and activation to safeguard undifferentiated spermatogonia fate |
title_sort | bmi1 fine-tunes gene repression and activation to safeguard undifferentiated spermatogonia fate |
topic | Cell and Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10164956/ https://www.ncbi.nlm.nih.gov/pubmed/37169021 http://dx.doi.org/10.3389/fcell.2023.1146849 |
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