Abstract
Switch/sucrose non-fermentable (SWI/SNF)-related matrix-associated actin-dependent regulator of chromatin (SMARC) subfamily B member 1 (SMARCB1) is a core subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, one of the adenosine triphosphate (ATP)-dependent chromatin remodeler complexes. The unique role of SMARCB1 has been reported in various cellular contexts. Here, we focused on the general role of the ubiquitous expression of SMARCB1 in a normal cell state. We selected ARPE19 (human primary retinal pigment epithelium) and IMR90 (from human fetal lung fibroblasts) cell lines as they have completely different contexts. Furthermore, although these cell lines have been immortalized, they are relatively close to normal human cells. The loss of SMARCB1 in ARPE19 and IMR90 cells reduced cell cycle progression via the upregulation of P21. Transcriptome analysis followed by SMARCB1 knockdown in both cell lines revealed that SMARCB1 was not only involved in cell maintenance but also conferred immunomodulation. Of note, SMARCB1 bound to interleukin (IL) 6 promoter in a steady state and dissociated in an active immune response state, suggesting that SMARCB1 was a direct repressor of IL6, which was further confirmed via loss- and gain-of-function studies. Taken together, we demonstrated that SMARCB1 is a critical gatekeeper molecule of the cell cycle and immune response.
Highlights
Chromatin-remodeling, which causes changes in chromatin structure, is essential for regulating the potential for gene expression [1]
We found a significant SMARCB1 peak around the IL6 promoter in human fibroblast (Figure 4c), and it was further confirmed by chromatin immunoprecipitation (ChIP) PCR that a decrease in SMARCB1 binding and an increase in active histone marker H3K4me3 occurred simultaneously with SMARCB1 loss in ARPE19 (Figure 4d,e), suggesting that SMARCB1 inhibited IL6 transcription when cells were in a steady state, thereby reducing the unnecessary immune response of the cell
This study revealed the role of SMARCB1 in the normal cell state
Summary
Chromatin-remodeling, which causes changes in chromatin structure, is essential for regulating the potential for gene expression [1]. SWI/SNF-related matrix-associated actin-dependent regulator of chromatin (SMARC) subfamily B member 1 (SMARCB1; SWI/SNF chromatin-remodeling complex subunit SNF5, BRG1-associated factor (BAF) 47, and integrase interactor 1 (INI1)), one of the core subunits of SWI/SNF, remains unchanged and is ubiquitously expressed [11]. ARPE19 evolved from human primary RPE (retinal pigment epithelium) cells that spontaneously immortalized [22], and this cell line is extremely useful for studying retinoid metabolism or RPE-specific gene expression [23]. The BAF complex is required to maintain the open conformation of the IFN target promoter [32] While these studies have presented the relationship between the SWI/SNF complex and the immune response, further research is necessary to elucidate the molecular network between two. SMARCB1 was associated with cell cycle regulation and immune response for cellular maintenance in normal cells
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