Transcriptional coactivator PGC-1α contributes to decidualization by forming a histone-modifying complex with C/EBPβ and p300

• Main Authors: Doi-Tanaka, Y. (Author), Fujimura, T. (Author), Maekawa, R. (Author), Mihara, Y. (Author), Sato, S. (Author), Shirafuta, Y. (Author), Sugino, N. (Author), Takagi, H. (Author), Taketani, T. (Author), Tamura, H. (Author), Tamura, I. (Author)
• Format: Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology Inc. 2022
• Subjects: Acetylation; Binding sites; Binding-sites; Coactivators; Cytology; Enhancer-binding proteins; Epigenomics; Genes encoding; Insulin-like growth factor binding protein-1; Peroxisome proliferator-activated receptor; Proteins; Stromal cells; Transcription; Transcriptional co-activators
• Online Access: View Fulltext in Publisher

 We previously reported that CCAAT/enhancer-binding protein beta (C/EBPβ) is the pioneer factor inducing transcription enhancer mark H3K27 acetylation (H3K27ac) in the promoter and enhancer regions of genes encoding insulin-like growth factor–binding protein-1 (IGFBP-1) and prolactin (PRL) and that this contributes to decidualization of human endometrial stromal cells (ESCs). Peroxisome proliferator–activated receptor gamma coactivator 1-alpha (PGC-1α; PPARGC1A) is a transcriptional coactivator known to regulate H3K27ac. However, although PGC-1α is expressed in ESCs, the potential role of PGC-1α in mediating decidualization is unclear. Here, we investigated the involvement of PGC-1α in the regulation of decidualization. We incubated ESCs with cAMP to induce decidualization and knocked down PPARGC1A to inhibit cAMP-induced expression of IGFBP-1 and PRL. We found cAMP increased the recruitment of PGC-1α and p300 to C/EBPβ-binding sites in the promoter and enhancer regions of IGFBP-1 and PRL, corresponding with increases in H3K27ac. Moreover, PGC-1α knockdown inhibited these increases, suggesting PGC-1α forms a histone-modifying complex with C/EBPβ and p300 at these regions. To further investigate the regulation of PGC-1α, we focused on C/EBPβ upstream of PGC-1α. We found cAMP increased C/EBPβ recruitment to the novel enhancer regions of PPARGC1A. Deletion of these enhancers decreased PGC-1α expression, indicating that C/EBPβ upregulates PGC-1α expression by binding to novel enhancer regions. In conclusion, PGC-1α is upregulated by C/EBPβ recruitment to novel enhancers and contributes to decidualization by forming a histone-modifying complex with C/EBPβ and p300, thereby inducing epigenomic changes in the promoters and enhancers of IGFBP-1 and PRL. © 2022 THE AUTHORS.