Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, US.
Endocrinology. 2020 Jun 1;161(6). doi: 10.1210/endocr/bqaa070.
The transcription factor GATA2 is important for endometrial stromal cell decidualization in early pregnancy. Progesterone receptor (PGR) is also critical during decidualization but its interaction with GATA2 in regulating genes and pathways necessary for decidualization in human endometrium are unclear. RNA-sequencing (RNA-seq) was performed to compare gene expression profiles (n = 3), and chromatin immunoprecipitation followed by sequencing (ChIP-seq) using an antibody against GATA2 (n = 2) was performed to examine binding to target genes in human endometrial stromal cells undergoing in vitro decidualization (IVD including estrogen, progestin, and 3',5'-cyclic AMP analogue) or vehicle treatment. We identified 1232 differentially expressed genes (DEGs) in IVD vs vehicle. GATA2 cistrome in IVD-treated cells was enriched with motifs for GATA, ATF, and JUN, and gene ontology analysis of GATA2 cistrome revealed pathways that regulate cholesterol storage, p38 mitogen-activated protein kinase, and the c-Jun N-terminal kinase cascades. Integration of RNA-seq and ChIP-seq data revealed that the PGR motif is highly enriched at GATA2 binding regions surrounding upregulated genes in IVD-treated cells. The integration of a mined public PGR cistrome in IVD-treated human endometrial cells with our GATA2 cistrome showed that GATA2 binding was significantly enhanced at PGR-binding regions in IVD vs vehicle. Interrogating 2 separate ChIP-seq data sets together with RNA-seq revealed integration of GATA2 and PGR action to coregulate biologic processes during decidualization of human endometrial stromal cells, specifically via WNT activation and stem cell differentiation pathways. These findings reveal the key pathways that are coactivated by GATA2 and PGR that may be therapeutic targets for supporting implantation and early pregnancy.
转录因子 GATA2 对于早孕时子宫内膜基质细胞的蜕膜化很重要。孕激素受体（PGR）在蜕膜化过程中也很关键，但它与 GATA2 相互作用，调节人类子宫内膜蜕膜化所需的基因和途径尚不清楚。我们进行了 RNA 测序（RNA-seq）以比较基因表达谱（n = 3），并使用针对 GATA2 的抗体进行了染色质免疫沉淀测序（ChIP-seq）（n = 2），以检查在体外蜕膜化（包括雌激素、孕激素和 3'，5'-环磷酸腺苷类似物）或载体处理的人子宫内膜基质细胞中靶基因的结合情况。我们在 IVD 与载体的比较中鉴定出 1232 个差异表达基因（DEGs）。在 IVD 处理的细胞中，GATA2 顺式作用元件富含 GATA、ATF 和 JUN 的基序，GATA2 顺式作用元件的基因本体分析显示了调节胆固醇储存、p38 丝裂原激活蛋白激酶和 c-Jun N 末端激酶级联的途径。RNA-seq 和 ChIP-seq 数据的整合表明，PGR 基序在 IVD 处理细胞中上调基因周围的 GATA2 结合区域高度富集。将在 IVD 处理的人子宫内膜细胞中挖掘的公共 PGR 顺式作用元件与我们的 GATA2 顺式作用元件整合在一起，表明与载体相比，在 IVD 中 GATA2 结合在 PGR 结合区域显著增强。一起分析 2 个独立的 ChIP-seq 数据集和 RNA-seq 揭示了 GATA2 和 PGR 作用的整合，以在人类子宫内膜基质细胞的蜕膜化过程中共同调节生物学过程，特别是通过 WNT 激活和干细胞分化途径。这些发现揭示了 GATA2 和 PGR 共同激活的关键途径，这些途径可能是支持着床和早期妊娠的治疗靶点。
