Black women experience a disproportionate impact of uterine fibroids compared to White women, including earlier diagnosis, higher frequency, and more severe symptoms. The etiology underlying this racial disparity remains elusive. The aim of this study was to evaluate the molecular differences in normal myometrium (fibroid-free uteri) and at-risk myometrium (fibroid-containing uteri) tissues in Black and White women. We conducted whole-genome RNA-seq on normal and at-risk myometrium tissues obtained from both self-identified Black and White women (not Hispanic or Latino) to determine global gene expression profiles and to conduct enriched pathway analyses (n=3 per group). We initially assessed the differences within the same type of tissue (normal or at-risk myometrium) between races. Subsequently, we analyzed the transcriptome of normal myometrium compared to at-risk myometrium in each race and determined the differences between them. We validated our findings through real-time PCR (sample size range=5–12), western blot (sample size range=5–6), and immunohistochemistry techniques (sample size range=9–16). The transcriptomic analysis revealed distinct profiles between Black and White women in normal and at-risk myometrium tissues. Interestingly, genes and pathways related to extracellular matrix and mechanosensing were more enriched in normal myometrium from Black than White women. Transcription factor enrichment analysis detected greater activity of the serum response transcription factor positional motif in normal myometrium from Black compared to White women. Furthermore, we observed increased expression levels of myocardin-related transcription factor-serum response factor and the serum response factor in the same comparison. In addition, we noted increased expression of both mRNA and protein levels of vinculin, a target gene of the serum response factor, in normal myometrium tissues from Black women as compared to White women. Importantly, the transcriptomic profile of normal to at-risk myometrium conversion differs between Black and White women. Specifically, we observed that extracellular matrix–related pathways are involved in the transition from normal to at-risk myometrium and that these processes are exacerbated in Black women. We found increased levels of Tenascin C, type I collagen alpha 1 chain, fibronectin, and phospho-p38 MAPK (Thr180/Tyr182, active) protein levels in at-risk over normal myometrium tissues from Black women, whereas such differences were not observed in samples from White women. These findings indicate that the racial disparities in uterine fibroids may be attributed to heightened production of extracellular matrix in the myometrium in Black women, even before the tumors appear. Future research is needed to understand early life determinants of the observed racial differences.

中文翻译：

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细胞外基质相关途径的改变加速了黑人女性从正常子宫肌层向肌瘤前子宫肌层的转变


与白人女性相比，黑人女性受到子宫肌瘤的影响更大，包括更早诊断、更高频率和更严重的症状。这种种族差异背后的病因仍然难以捉摸。本研究的目的是评估黑人和白人女性正常子宫肌层（无肌瘤子宫）和危险肌层（含肌瘤子宫）组织的分子差异。我们对从自我认定的黑人和白人女性（非西班牙裔或拉丁裔）获得的正常和有风险的子宫肌组织进行全基因组 RNA-seq，以确定全局基因表达谱并进行富集通路分析（每组 n=3） ）。我们最初评估了种族之间同一类型组织（正常或有风险的子宫肌层）内的差异。随后，我们分析了每个种族中正常子宫肌层与危险子宫肌层的转录组，并确定了它们之间的差异。我们通过实时 PCR（样本量范围=5-12）、蛋白质印迹（样本量范围=5-6）和免疫组织化学技术（样本量范围=9-16）验证了我们的发现。转录组分析揭示了黑人和白人女性在正常和高危子宫肌组织中的不同特征。有趣的是，与细胞外基质和机械传感相关的基因和通路在黑人女性的正常子宫肌层中比白人女性更丰富。转录因子富集分析发现，与白人女性相比，黑人正常子宫肌层中血清反应转录因子位置基序的活性更高。此外，在同一比较中，我们观察到心肌素相关转录因子-血清反应因子和血清反应因子的表达水平增加。 此外，我们注意到，与白人女性相比，黑人女性正常子宫肌组织中纽蛋白（血清反应因子的靶基因）的 mRNA 和蛋白水平表达增加。重要的是，黑人和白人女性正常子宫肌层向高危子宫肌层转化的转录组学特征不同。具体来说，我们观察到细胞外基质相关途径参与从正常子宫肌层向危险子宫肌层的转变，并且这些过程在黑人女性中加剧。我们发现，与黑人女性的正常子宫肌组织相比，处于危险中的肌腱蛋白 C、I 型胶原 α 1 链、纤连蛋白和磷酸化 p38 MAPK（Thr180/Tyr182，活性）蛋白水平有所增加，而在黑人女性中未观察到这种差异。白人女性的样本。这些发现表明，子宫肌瘤的种族差异可能归因于黑人女性子宫肌层细胞外基质的产生增加，甚至在肿瘤出现之前。未来的研究需要了解所观察到的种族差异的早期生活决定因素。