Wnt3a disrupts GR-TEAD4-PPARγ2 positive circuits and cytoskeletal rearrangement in a β-catenin-dependent manner during early adipogenesis

Abstract

Adipogenesis is a process which induces or represses many genes in a way to drive irreversible changes of cell phenotypes; lipid accumulation, round cell-shape, secreting many adipokines. As a master transcription factor (TF), PPARγ2 induces several target genes to orchestrate these adipogenic changes. Thus induction of Pparg2 gene is tightly regulated by many adipogenic and also anti-adipogenic factors. Four hours after the treatment of adipogenic hormones, more than fifteen TFs including glucocorticoid receptor (GR), C/EBPβ and AP-1 cooperatively bind the promoter of Pparg2 gene covering 400 bps, termed “hotspot”. In this study, we show that TEA domain family transcription factor (TEAD)4 reinforces occupancy of both GR and C/EBPβ on the hotspot of Pparg2 during early adipogenesis. Our findings that TEAD4 requires GR for its expression and for the ability to bind its own promoter and the hotspot region of Pparg2 gene indicate that GR is a common component of two positive circuits, which regulates the expression of both Tead4 and Pparg2. Wnt3a disrupts these mutually related positive circuits by limiting the nuclear location of GR in a β-catenin dependent manner. The antagonistic effects of β-catenin extend to cytoskeletal remodeling during the early phase of adipogenesis. GR is necessary for the rearrangements of both cytoskeleton and chromatin of Pparg2, whereas Wnt3a inhibits both processes in a β-catenin-dependent manner. Our results suggest that hotspot formation during early adipogenesis is related to cytoskeletal remodeling, which is regulated by the antagonistic action of GR and β-catenin, and that Wnt3a reinforces β-catenin function.

Glucocorticoid Receptor Signaling Activates TEAD4 to Promote Breast Cancer Progression

“…2B-D). As GR regulates genes mainly by binding to their promoters (26), and GR regulates TEAD4 transcription during adipogenesis (18). We hypothesized that TEAD4 is also a direct target of GR during breast tumorigenesis.…”

“…More importantly, TEAD4 nuclear localization positively autoregulates its own transcription and increases its protein level in the trophectoderm lineage, and the high TEAD4 concentration facilitates its nuclear localization as a positive feedback response (17). Recently, it has been reported that the glucocorticoid receptor (GR) binds to the promoter of TEAD4 to regulate TEAD4 transcription during adipogenesis (18). The activity of TEADs is also regulated by its cofactors.…”

Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells

“…In the canonical Wnt pathway, Wnt ligand inactivates GSK3 via phosphorylation to inhibit the phosphorylation of β-Catenin, leading the latter to stabilize and translocate into the nucleus in order to transcribe downstream target genes (48). This pathway is well established to inhibit adipogenesis (49,50) and promote bone formation (51-53); while upregulation of non-canonical associated proteins induces Runx2 expression (54,55), the main osteoblastogenic transcriptional factor. Thus, Adipsin likely inhibits Wnt signaling in order to determine the differentiation fate of BMSCs.…”

Table_1.DOCX

“…For each treatment, 5 images were taken randomly within each chamber via a Bio-Rad ZOE Fluorescent Cell Imager using a 20X objective. F-actin structures in individual cells were observed and categorized into three types (Park et al, 2019). Quantification of each type of F-actin structure was analyzed using Image J software (Park et al, 2019).…”

“…F-actin structures in individual cells were observed and categorized into three types (Park et al, 2019). Quantification of each type of F-actin structure was analyzed using Image J software (Park et al, 2019). Briefly, stress fibers, where F-actin stress fibers were observed both in the nucleus and cytoplasm; transition state fibers, where F-actin stress fibers were observed only in the cytoplasm; cortical structure fibers, where F-actin fibers were observed near the cellular membrane as cortical structures.…”