Kalantari Shadi, Saadat Varnosfaderani Ameneh, Ramezanali Fariba, Amirchaghmaghi Elham, Shahhoseini Maryam
Department of Cell and Molecular Biology Science, Faculty of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran.
Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.
Int J Fertil Steril. 2025 Mar 11;19(2):151-156. doi: 10.22074/ijfs.2024.2026438.1659.
Endometriosis is an estrogen-dependent disease. Cytochrome P450 aromatase which encoded by CYP19A1 is a key enzyme in the pathway of estrogen biosynthesis. cAMP response element (CRE) binding protein (CREB) and cAMP response element modulator (CREM), two members of the CREB family have important roles in the regulation of steroidogenic gene expression. CREB and CREM form homo and heterodimers for binding to the CRE sequence in the promoter of the gene and regulate its expression. CREB regulated transcription coactivator 2 (CRTC2) is a CREB coactivator and regulates aromatase gene expression via binding to the CREB. Inducible cAMP early repressor (ICER) is one of inhibitory isoforms that represses cAMP-induced transcription. Therefore, in this study, we decided to examine the expression levels of and genes and also the binding of ICER to the promoter II of the aromatase gene in endometriosis.
In this case-control study, ectopic and eutopic endometrial tissues of women with endometriosis and endometrial control samples were collected. Real-time polymerase chain reaction (PCR) technique was used for quantitative gene expression of and . For protein-DNA interaction analysis, soluble chromatin was extracted, and chromatin immunoprecipitation (ChIP) coupled with real-time PCR was performed to quantify the binding of ICER to promoter II.
Gene expression levels of and were significantly increased in ectopic lesions compared with control endometrial samples. In addition, the binding of ICER to CYP19A1 promoter II was significantly decreased in ectopic and eutopic samples compared to the controls.
The overexpression of and in the endometriotic tissue samples and decreased binding of ICER to the prompter II in ectopic and eutopic samples may contribute to the pathogenesis of endometriosis via their regulatory role in the expression of estrogen biosynthesis enzymes.
子宫内膜异位症是一种雌激素依赖性疾病。由CYP19A1编码的细胞色素P450芳香化酶是雌激素生物合成途径中的关键酶。cAMP反应元件（CRE）结合蛋白（CREB）和cAMP反应元件调节剂（CREM）是CREB家族的两个成员，在类固醇生成基因表达的调控中起重要作用。CREB和CREM形成同二聚体和异二聚体，与基因启动子中的CRE序列结合并调节其表达。CREB调节的转录共激活因子2（CRTC2）是一种CREB共激活因子，通过与CREB结合来调节芳香化酶基因的表达。诱导型cAMP早期阻遏物（ICER）是抑制cAMP诱导转录的抑制性异构体之一。因此，在本研究中，我们决定检测子宫内膜异位症中相关基因的表达水平以及ICER与芳香化酶基因启动子II的结合情况。
在这项病例对照研究中，收集了子宫内膜异位症患者的异位和在位子宫内膜组织以及子宫内膜对照样本。采用实时聚合酶链反应（PCR）技术对相关基因进行定量表达分析。对于蛋白质-DNA相互作用分析，提取可溶性染色质，并进行染色质免疫沉淀（ChIP）结合实时PCR，以定量ICER与启动子II的结合情况。
与对照子宫内膜样本相比，异位病变中相关基因的表达水平显著升高。此外，与对照组相比，异位和在位样本中ICER与CYP19A1启动子II的结合显著减少。
子宫内膜异位症组织样本中相关基因的过表达以及异位和在位样本中ICER与启动子II结合的减少，可能通过其对雌激素生物合成酶表达的调节作用，参与子宫内膜异位症的发病机制。
