RNA-sequencing reveals novel molecular mechanisms of endometriosis lesion development in a mouse model. RNA-sequencing reveals novel molecular mechanisms of endometriosis lesion development in a mouse model

Our understanding of molecular mechanisms contributing to the pathophysiology of endometriosis, and their upstream regulators, remains limited. Using a C57Bl/6 mouse model of endometriosis in which decidualized endometrial tissue fragments are transferred to subcutaneous sites in recipient mice to mimic endometriosis lesions, we have generated a comprehensive profile of gene expression in decidualized endometrial tissue (n=4), and endometriosis-like lesions at Day 7 (n=4) and Day 14 (n=4) of lesion formation. High throughput mRNA sequencing allowed identification of genes and pathways involved in the initiation and progression of endometriosis-like lesions. We found distinct patterns of gene expression with substantial differences between the lesions and the decidualized endometrium from which they arose, but no differentially expressed genes between the two lesion timepoints. The transcriptional changes at the outset of lesion formation indicated substantial upregulation of immune response-associated canonical pathways. Pathway enrichment analysis indicates multiple potential endogenous upstream regulators, and reveals multiple gene candidates not previously implicated in endometriosis lesion formation suggesting these mediators may have novel roles in disease progression. Collectively, the provided data will be a valuable resource to inform research on the molecular mechanisms contributing to endometriosis development. Overall design: We performed gene expression profiling using RNA-seq of donor decidualized endometrium (n=4), endometriosis-like lesions at Day 7 (n=4) and Day 14 (n=4) in a C57BL/6 subcutaneous mouse model of endometriosis. There are two additional experimental groups (miR-155 deficient and miR-223 deficient mouse models) also included in this dataset giving a total of 36 samples (4 biological replicates at each timepoint, 12 samples per genotype) These additional samples will reported in a separate manuscript to elucidate the impact of microRNA modulation in endometriosis-like lesion development in mice.

目前学界对子宫内膜异位症（endometriosis）病理生理学相关分子机制及其上游调控因子的认知仍十分有限。本研究采用C57Bl/6子宫内膜异位症小鼠模型，将蜕膜化子宫内膜组织（decidualized endometrial tissue）片段移植至受体小鼠皮下位点以模拟子宫内膜异位病灶，分别对蜕膜化子宫内膜组织（n=4）、病灶形成第7天（n=4）及第14天（n=4）的子宫内膜异位样病灶进行了全面的基因表达谱分析。通过高通量mRNA测序（high throughput mRNA sequencing），我们鉴定出了参与子宫内膜异位样病灶起始与进展的基因及通路。研究发现病灶与起源的蜕膜化子宫内膜组织间存在显著的基因表达差异模式，但两个病灶时间点之间未检测到差异表达基因。病灶形成初期的转录组变化显示，与免疫应答相关的经典通路出现显著上调。通路富集分析（pathway enrichment analysis）揭示了多种潜在内源性上游调控因子，并鉴定出多个此前未被发现与子宫内膜异位症病灶形成相关的候选基因，提示这些调控介质可能在疾病进展中发挥全新作用。综上，本数据集提供的数据将成为研究子宫内膜异位症发生发展分子机制的宝贵资源。实验设计概述：本研究在C57BL/6子宫内膜异位症皮下小鼠模型中，通过RNA测序（RNA-seq）对供体蜕膜化子宫内膜组织（n=4）、病灶形成第7天（n=4）及第14天（n=4）的子宫内膜异位样病灶进行了基因表达谱分析。本数据集还包含另外两个实验组：miR-155缺陷型与miR-223缺陷型小鼠模型，总计36个样本（每个时间点含4个生物学重复，每种基因型含12个样本）。上述额外样本将在另一篇论文中进行报道，以阐明微小RNA（microRNA）调控对小鼠子宫内膜异位样病灶发育的影响。