Transcriptional coactivator PGC-1α contributes to decidualization by forming a histone-modifying complex with C/EBPβ and p300
- PMID: 35358514
- PMCID: PMC9048111
- DOI: 10.1016/j.jbc.2022.101874
Transcriptional coactivator PGC-1α contributes to decidualization by forming a histone-modifying complex with C/EBPβ and p300
Abstract
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.
Keywords: CCAAT/enhancer-binding protein beta (C/EBPβ); E1A-binding protein p300 (p300); decidualization; endometrial stromal cell; epigenetics; genome editing; histone acetylation; peroxisome proliferator–activated receptor gamma coactivator 1-alpha (PGC-1α).
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
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