The BRG1 ATPase of chromatin remodeling complexes is involved in modulation of mesenchymal stem cell senescence through RB–P53 pathways

Abstract

We focused our attention on brahma-related gene 1 (BRG1), the ATPase subunit of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex, and analyzed its role in mesenchymal stem cell (MSC) biology. We hypothesized that deviation from the correct concentration of these proteins, which act at the highest level of gene regulation, may be deleterious for cells. We wanted to know what would happen if a cell had to cope with altered regulation of gene expression, either by upregulation or downregulation of BRG1. We assumed that cells would try to restore homeostasis or, alternatively, that the event could trigger senescence/apoptosis phenomena. To this end, in MSCs, we silenced BRG1gene. Knockdown of BRG1 expression induced a significant increase in senescent cells and decrease in apoptotic cells. It is interesting that BRG1 downregulation also induced an increase in heterochromatin. At the molecular level, these phenomena were associated with activation of retinoblastoma-like protein 2 (RB2)/P130-and P53-related pathways. Senescence was accompanied by reduced expression of some stemness-related genes. This is consistent with our previous research, which showed that BRG1 upregulation by ectopic expression also induced senescence processes. Together, these data suggest that BRG1 belongs to a class of genes whose expression is tightly regulated; hence, subtle alterations in BRG1 activity seem to negatively affect mechanisms regulating chromatin status and, in turn, impair cellular physiology.

Long non-coding RNA urothelial carcinoma associated 1 induces cell replication by inhibiting BRG1 in 5637 cells

“…If senescence is inhibited, however, cells become prone to carcinogenesis. Previous studies have shown that overexpression of BRG1 may lead to cellular senescence (28). Additionally, BRG1 is required for formation of senescence-associated heterochromatin foci (SAHF) (20).…”

Involvement of Telomerase Reverse Transcriptase in Heterochromatin Maintenance

“…In addition, several laboratories have demonstrated that TERT forms complexes independent of the telomerase RNA hTERC (9,11,15). Specifically, we along with others have found that hTERT binds BRG1 and NS and that this complex regulates both gene transcription (11) and stem cell function in normal and malignant cells (15,39,40) in a manner independent of telomere maintenance. Here, we report that the levels of this complex are increased in mitotic cells but not in asynchronously cycling cells (41) and that suppressing each of the members of this complex arrests cells in mitosis.…”

Multiple facets of histone variant H2AX: a DNA double-strand-break marker with several biological functions

“…Interestingly, H2AX depletion suppressed the DDR-dependent senescence-associated growth arrest and IL-6 secretion, indicating that the activated DDR signalling during senescence has a functional role, mediated also by γH2AX presence. Supporting the idea that senescent PDDF are a signature of stable chromatin alterations, rather than classical DSBs, changes in chromatin organization are sufficient to induce senescence and are associated with increase in H2AX phosphorylation (104,105). Recently our group described for the first time the presence of PDDF in adult stem cells (106), thus extending the impact of this non-canonical H2AX role in senescence maintenance to undifferentiated cells.…”