Guo Mengbiao, Fang Zhengwen, Chen Bohong, Songyang Zhou, Xiong Yuanyan
Key Laboratory of Gene Engineering of the Ministry of Education, Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China.
iScience. 2023 Jan 18;26(2):105997. doi: 10.1016/j.isci.2023.105997. eCollection 2023 Feb 17.
The active X chromosome in mammals is upregulated to balance its dosage to autosomes during evolution. However, it is elusive why the known dosage compensation machinery showed uneven and small influence on X genes. Here, based on >20,000 transcriptomes, we identified two X gene groups (ploidy-sensitive [PSX] and ploidy-insensitive [PIX]), showing distinct but evolutionarily conserved dosage compensations (termed XAR). We demonstrated that XAR-PIX was downregulated whereas XAR-PSX upregulated at both RNA and protein levels across cancer types, in contrast with their trends during stem cell differentiation. XAR-PIX, but not XAR-PSX, was lower and correlated with autoantibodies and inflammation in patients of lupus, suggesting that insufficient dosage of PIX genes contribute to lupus pathogenesis. We further identified and experimentally validated two XAR regulators, and . Collectively, we provided insights into X dosage compensation in mammals and demonstrated different regulation of PSX and PIX and their pathophysiological roles in human diseases.
在进化过程中，哺乳动物的活性X染色体上调，以平衡其与常染色体的剂量。然而，已知的剂量补偿机制为何对X基因的影响不均衡且较小，这一点尚不清楚。在此，基于20000多个转录组，我们鉴定出两个X基因组（倍性敏感[PSX]和倍性不敏感[PIX]），它们表现出不同但在进化上保守的剂量补偿（称为XAR）。我们证明，与干细胞分化过程中的趋势相反，XAR-PIX在所有癌症类型的RNA和蛋白质水平均下调，而XAR-PSX上调。XAR-PIX而非XAR-PSX在狼疮患者中水平较低，且与自身抗体和炎症相关，这表明PIX基因剂量不足导致狼疮发病机制。我们进一步鉴定并通过实验验证了两个XAR调节因子。总体而言，我们深入了解了哺乳动物中的X剂量补偿，并证明了PSX和PIX的不同调节及其在人类疾病中的病理生理作用。
