title: BAF180 regulates cellular senescence and hematopoietic stem cell homeostasis through p21.
abstract: 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.
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hyemin
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Fangyan
authors.initials: F
authors.lastname: Dai
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhuang
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Zhen-Dong
authors.initials: ZD
authors.lastname: Xiao
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jongchan
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yilei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Program of Genes and Development, The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA.|Program of Cancer Biology, The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Program of Genes and Development, The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA.
authors.forename: M James
authors.initials: MJ
authors.lastname: You
authors.affiliation: Department of Cardiac Surgery, Cardiovascular Research Center, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Program of Genes and Development, The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA.|Program of Cancer Biology, The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA.
authors.forename: Boyi
authors.initials: B
authors.lastname: Gan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000235:genetics; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D024002:HMGB Proteins / Q000235:genetics* / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics*; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D024002:HMGB Proteins; C496872:Pbrm1 protein, mouse; D014157:Transcription Factors
keywords: BAF180; Gerotarget; cellular senescence; hematopoietic stem cell; p21