BAF180 regulates cellular senescence and hematopoietic stem cell homeostasis through p21.
BAF180 regulates cellular senescence and hematopoietic stem cell homeostasis through p21.
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DOI：
10.18632/oncotarget.8102
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发表时间：
2016-04-12
期刊：
影响因子：
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通讯作者：
Gan B
中科院分区：
文献类型：
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作者：
Lee H;Dai F;Zhuang L;Xiao ZD;Kim J;Zhang Y;Ma L;You MJ;Wang Z;Gan B
BAF180（也称为 PBRM1）是 SWI/SNF 复合物的一个亚基，在染色质重塑和基因转录的调节中发挥着关键作用，并且在多种人类癌症中经常发生突变。然而，哺乳动物 BAF180 在体内肿瘤抑制和组织维持中的作用仍然很大程度上未知。在这里，我们使用条件体细胞敲除方法，探索了 BAF180 在小鼠中的细胞和有机体功能。原代小鼠胚胎成纤维细胞 (MEF) 中的 BAF180 缺失会引发严重的细胞周期停滞、细胞过早衰老，但不会影响 DNA 损伤反应或染色体完整性。虽然成年小鼠中 BAF180 的体细胞缺失不会引起肿瘤发展，但 BAF180 缺陷小鼠表现出造血系统缺陷，其特征是造血干细胞 (HSC) 逐渐减少、长期再增殖潜力缺陷和造血谱系发育畸变。 BAF180 缺失导致 MEF 和 HSC 中 p21 表达升高。从机制上讲，我们发现 BAF180 与 p21 启动子结合，并且 BAF180 缺失增强了与 p21 启动子转录激活相关的修饰组蛋白的结合。 p21 的缺失可挽救 BAF180 缺陷型 MEF 的细胞周期停滞和过早衰老，并部分挽救 BAF180 缺陷型小鼠的造血缺陷。总之，我们的研究确定 BAF180 是细胞衰老和 HSC 稳态的关键调节因子，它至少部分是通过 BAF180 介导的 p21 表达抑制来调节的。我们的结果还表明，BAF180 失活引发的衰老可能作为抑制 BAF180 缺陷相关肿瘤发展的故障保护机制，为进一步了解 BAF180 在肿瘤生物学中的功能提供了概念框架。
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.