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Impaired bone morphogenetic protein signaling pathways perturb decidualization in patients with endometriosis (Cut&Run-Seq)

ABSTRACT: It is hypothesized that impaired endometrial decidualization contributes to decreased fertility in endometriosis patients. To identify the molecular defects that underpin defective decidualization in endometriosis, we subjected endometrial stromal cells from healthy individuals or with endometriosis to time course in vitro decidualization with estradiol, progesterone, and 8-bromo-cyclic-AMP (EPC) for 2, 4, 6, or 8 days. Transcriptomic profiling identified novel differences in key pathways between normal and endometriosis, including defective bone morphogenetic protein (BMP) signaling (ID1, ID2, ID3, BMP6), altered iron transport (SLC40A1, TFRC), endometrial stem cell markers (CD44, SUSD2), and retinoid signaling pathways (RORB, ALDH1L1, RARA). Genome-wide binding analyses identified an altered genomic distribution of SMAD4 in decidualized stromal cells from endometriosis patients relative to normal individuals, with an overrepresentation of gene ontologies related to signaling by transforming growth factor β (TGFβ), neurotrophic tyrosine kinase receptors (NTRK), and nerve growth factor (NGF)-stimulated transcription. We found that direct SMAD1/5/4 target genes control FOXO, PI3K/AKT, and progesterone-mediated signaling in decidualizing cells and that BMP2 supplementation of patient-derived assembloids from endometriosis patients restored decidualization. In summary, transcriptomic and genomic profiling of patient-derived endometrial cells and assembloids identified that restoring BMP/SMAD1/5/4 signaling is crucial for engaging a robust decidualization program in women with endometriosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE243156 | GEO | 2024/02/17

REPOSITORIES: GEO

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Impaired bone morphogenetic protein signaling pathways perturb decidualization in patients with endometriosis (Time-course EPC studies)

Project description:It is hypothesized that impaired endometrial decidualization contributes to decreased fertility in endometriosis patients. To identify the molecular defects that underpin defective decidualization in endometriosis, we subjected endometrial stromal cells from healthy individuals or with endometriosis to time course in vitro decidualization with estradiol, progesterone, and 8-bromo-cyclic-AMP (EPC) for 2, 4, 6, or 8 days. Transcriptomic profiling identified novel differences in key pathways between normal and endometriosis, including defective bone morphogenetic protein (BMP) signaling (ID1, ID2, ID3, BMP6), altered iron transport (SLC40A1, TFRC), endometrial stem cell markers (CD44, SUSD2), and retinoid signaling pathways (RORB, ALDH1L1, RARA). Genome-wide binding analyses identified an altered genomic distribution of SMAD4 in decidualized stromal cells from endometriosis patients relative to normal individuals, with an overrepresentation of gene ontologies related to signaling by transforming growth factor β (TGFβ), neurotrophic tyrosine kinase receptors (NTRK), and nerve growth factor (NGF)-stimulated transcription. We found that direct SMAD1/5/4 target genes control FOXO, PI3K/AKT, and progesterone-mediated signaling in decidualizing cells and that BMP2 supplementation of patient-derived assembloids from endometriosis patients restored decidualization. In summary, transcriptomic and genomic profiling of patient-derived endometrial cells and assembloids identified that restoring BMP/SMAD1/5/4 signaling is crucial for engaging a robust decidualization program in women with endometriosis.

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