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Mitotic bookmarking by SWI/SNF subunits.

ABSTRACT: For cells to initiate and sustain a differentiated state, it is necessary that a 'memory' of this state is transmitted through mitosis to the daughter cells^1-3. Mammalian switch/sucrose non-fermentable (SWI/SNF) complexes (also known as Brg1/Brg-associated factors, or BAF) control cell identity by modulating chromatin architecture to regulate gene expression^4-7, but whether they participate in cell fate memory is unclear. Here we provide evidence that subunits of SWI/SNF act as mitotic bookmarks to safeguard cell identity during cell division. The SWI/SNF core subunits SMARCE1 and SMARCB1 are displaced from enhancers but are bound to promoters during mitosis, and we show that this binding is required for appropriate reactivation of bound genes after mitotic exit. Ablation of SMARCE1 during a single mitosis in mouse embryonic stem cells is sufficient to disrupt gene expression, impair the occupancy of several established bookmarks at a subset of their targets and cause aberrant neural differentiation. Thus, SWI/SNF subunit SMARCE1 has a mitotic bookmarking role and is essential for heritable epigenetic fidelity during transcriptional reprogramming.

SUBMITTER: Zhu Z

PROVIDER: S-EPMC10303083 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Mitotic bookmarking by SWI/SNF subunits.

Zhu Zhexin Z Chen Xiaolong X Guo Ao A Manzano Trishabelle T Walsh Patrick J PJ Wills Kendall M KM Halliburton Rebecca R Radko-Juettner Sandi S Carter Raymond D RD Partridge Janet F JF Green Douglas R DR Zhang Jinghui J Roberts Charles W M CWM

Nature 20230524 7963

For cells to initiate and sustain a differentiated state, it is necessary that a 'memory' of this state is transmitted through mitosis to the daughter cells<sup>1-3</sup>. Mammalian switch/sucrose non-fermentable (SWI/SNF) complexes (also known as Brg1/Brg-associated factors, or BAF) control cell identity by modulating chromatin architecture to regulate gene expression<sup>4-7</sup>, but whether they participate in cell fate memory is unclear. Here we provide evidence that subunits of SWI/SNF ac ...[more]

PMID: 37225980

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Project description:BackgroundThe switch/sucrose nonfermentable (SWI/SNF) complex is an evolutionarily conserved chromatin remodeling complex that displays dysfunction in many tumors, especially undifferentiated carcinoma. Cancer stem cells (CSC), a special type of undifferentiated cancer cells with stem cell-like properties, play an essential role in tumor cell proliferation, invasion, and metastasis. In undifferentiated gastric carcinomas, the association of SWI/SNF complexes with clinicopathological features, CSC phenotype, and the prognosis is not fully understood.MethodsWe collected a cohort of 21 patients with undifferentiated/dedifferentiated gastric carcinoma. We next performed immunohistochemistry staining for the five subunits of the SWI/SNF complex (ARID1A, ARID1B, SMARCA2, SMARCA4, and SMARCB1), and four mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6), as well as other markers such as p53, PD-L1, and cancer stem cell (CSC) markers (SOX2, SALL4). Then, we investigated the correlation of SWI/SNF complex subunits with clinicopathological characters and performed prognostic analysis.ResultsWe observed SMARCA2 loss in 12 cases (57.14%), followed by ARID1A (5 cases, 23.81%) and SMARCA4 (3 cases, 14.29%). Fourteen cases (66.67%) lost any one of the SWI/SNF complex subunits, including 3 cases with SMARCA2 and ARID1A co-loss, and 3 cases with SMARCA2 and SMARCA4 co-loss. Correlation analysis revealed that the CSC phenotype occurred more frequently in the SWI/SNF complex deficient group (P = 0.0158). Survival analysis revealed that SWI/WNF complex deficiency, undifferentiated status, CSC phenotype, and the loss of SMARCA2 and SMARCA4 resulted in worse survival. Univariate and multivariate Cox regression analyses screened out three independent factors associated with worse prognosis: undifferentiated status, SWI/SNF complex deficiency, and lymph node metastasis.ConclusionsThe SWI/SNF complex deficiency was more likely to result in a CSC phenotype and worse survival and was an independent prognostic factor in undifferentiated/dedifferentiated gastric carcinoma.

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Mitotic bookmarking by SWI/SNF subunits.

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Mitotic bookmarking by SWI/SNF subunits.

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