Sexual dimorphism represents a key concept in the comprehension of molecular processes guiding several sex-specific physiological and pathological mechanisms. It has been reported that genes involved in many disorders show a sex-dependent expression pattern. Moreover, the loss of Y chromosome (LOY), found to be a physiological age-driven phenomenon, has been linked to many neurodegenerative and autoimmune disorders, and to an increased cancer risk. These findings drove us towards the consideration that LOY may cause the de-regulation of disease specific networks, involving genes located in both autosomal and sex chromosomes. Exploiting the CRISPR/Cas9 and RNA-sequencing technologies, we generated a Y-deficient human cell line that has been investigated for its gene expression profile. Our results showed that LOY can influence the transcriptome displaying relevant enriched biological processes, such as cell migration regulation, angiogenesis and immune response. Interestingly, the ovarian follicle development pathway was found enriched, supporting the female-mimicking profile of male Y-depleted cells. This study, besides proposing a novel approach to investigate sex-biased physiological and pathological conditions, highlights new roles for the Y chromosome in the sexual dimorphism characterizing human health and diseases. Moreover, this analysis paves the way for the research of new therapeutic approaches for sex dimorphic and LOY-related diseases.

中文翻译：

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CRISPR/Cas9介导的Y染色体消除影响人类细胞转录组

性别二态性代表了理解指导多种性别特异性生理和病理机制的分子过程的关键概念。据报道，与许多疾病相关的基因表现出性别依赖性的表达模式。此外，Y染色体（LOY）的丢失被认为是一种生理年龄驱动的现象，与许多神经退行性和自身免疫性疾病以及癌症风险增加有关。这些发现促使我们考虑 LOY 可能导致疾病特异性网络的失调，涉及位于常染色体和性染色体的基因。利用 CRISPR/Cas9 和 RNA 测序技术，我们生成了 Y 缺陷型人类细胞系，并对其基因表达谱进行了研究。我们的结果表明，LOY 可以影响转录组，展示相关的丰富生物过程，例如细胞迁移调节、血管生成和免疫反应。有趣的是，我们发现卵巢卵泡发育途径丰富，支持男性 Y 耗尽细胞的女性模仿特征。这项研究除了提出了一种研究性别偏向的生理和病理条件的新方法之外，还强调了 Y 染色体在表征人类健康和疾病的性二态性中的新作用。此外，这一分析为性别二态性和 LOY 相关疾病的新治疗方法的研究铺平了道路。