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

We previously reported that CCAAT/enhancer-binding protein beta (C/EBP beta) is the pioneer factor inducing tran-scription 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-1 alpha; PPARGC1A) is a transcriptional coactivator known to regulate H3K27ac. However, although PGC-1 alpha is expressed in ESCs, the potential role of PGC-1 alpha in mediating decidualization is un-clear. Here, we investigated the involvement of PGC-1 alpha 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-1 alpha and p300 to C/EBP beta-binding sites in the promoter and enhancer regions of IGFBP-1 and PRL, corresponding with increases in H3K27ac. Moreover, PGC-1 alpha knockdown inhibited these increases, suggesting PGC-1 alpha forms a histone-modifying complex with C/EBP beta and p300 at these regions. To further investigate the regulation of PGC-1 alpha, we focused on C/EBP beta upstream of PGC-1 alpha. We found cAMP increased C/EBP beta recruitment to the novel enhancer regions of PPARGC1A. Deletion of these enhancers decreased PGC-1 alpha expression, indicating that C/EBP beta upregulates PGC-1 alpha expression by binding to novel enhancer regions. In conclusion, PGC-1 alpha is upregulated by C/EBP beta recruitment to novel enhancers and contributes to decidualization by forming a histone-modifying complex with C/EBP beta and p300, thereby inducing epigenomic changes in the promoters and enhancers of IGFBP-1 and PRL.