Filamin A suppresses the expression of ribosomal protein genes by controlling the activity of an EGR1-Sp1-GCN5/PCAF pathway in human cells

Abstract

Human ribosome biogenesis requires four types of rRNA molecules and almost eighty cytoplasmic ribosomal proteins (CRPs) to be assembled together. . In the previous work, we showed that cytoskeletal filamin A (FLNA) can suppress rRNA expression in human cells. Thus, we hypothesized that FLNA can modulate the expression of CRPs because human cells have to coordinate cellular ribosome biogenesis. Here, we show that the absence of FLNA enhances the expression of most CRP genes assayed in the work, whereas the presence of FLNA dampens the expression of these CRP genes in several transformed cell types. The analysis of RNA-seq data revealed that FLNA silencing activated the expression of almost all CRPs and many mitochondrial RP genes in SaOS2 cells. These results indicate that FLNA acts as a negative regulator in CRP expression in human cells. Mechanistically, FLNA inhibits the expression of GCN5 and PCAF, which consequently impedes the occupancies of GCN5, PCAF, andH3K9ac at CRP gene loci. Both GCN5 and PCAF participates in the regulation of CRP expression either mediated by FLNA or independently. We show that FLNA silencing activates Sp1 expression and the activation of Sp1 stimulates the expression of Gcn5 and Pcaf genes. Further analysis revealed that EGR1 can bind the Sp1 gene promoter and activate Sp1 transcription. Collectively, this study revealed an EGR1-Sp1-GCN5/PCAF pathway by which FLNA modulates the expression of CRP genes. These findings shed light on how human cells coordinate the expression of CRP genes during ribosomal biogenesis.