College of Health and Life Sciences, Qatar Foundation, Hamad Bin Khalifa University, Doha, Qatar.
College of Science and Engineering, Hamad Bin Khalifa University, Doha, Qatar.
Epigenetics. 2023 Dec;18(1):2229203. doi: 10.1080/15592294.2023.2229203.
The human ribosomal DNA (rDNA) copy number (CN) has been challenging to analyse, and its sequence has been excluded from reference genomes due to its highly repetitive nature. The 45S rDNA locus encodes essential components of the cell, nevertheless rDNA displays high inter-individual CN variation that could influence human health and disease. CN alterations in rDNA have been hypothesized as a possible factor in autism spectrum disorders (ASD) and were shown to be altered in Schizophrenia patients. We tested whether whole-genome bisulphite sequencing can be used to simultaneously quantify rDNA CN and measure DNA methylation at the 45S rDNA locus. Using this approach, we observed high inter-individual variation in rDNA CN, and limited intra-individual copy differences in several post-mortem tissues. Furthermore, we did not observe any significant alterations in rDNA CN or DNA methylation in Autism Spectrum Disorder (ASD) brains in 16 ASD vs 11 control samples. Similarly, no difference was detected when comparing neurons form 28 Schizophrenia (Scz) patients vs 25 controls or oligodendrocytes from 22 Scz samples vs 20 controls. However, our analysis revealed a strong positive correlation between CN and DNA methylation at the 45S rDNA locus in multiple tissues. This was observed in brain and confirmed in small intestine, adipose tissue, and gastric tissue. This should shed light on a possible dosage compensation mechanism that silences additional rDNA copies to ensure homoeostatic regulation of ribosome biogenesis.
人类核糖体 DNA(rDNA) 的拷贝数(CN) 一直难以分析，由于其高度重复的性质，其序列已被排除在参考基因组之外。45S rDNA 基因座编码细胞的必需成分，然而 rDNA 显示出高度的个体间 CN 变异，这可能会影响人类的健康和疾病。rDNA 中的 CN 改变被假设为自闭症谱系障碍(ASD) 的一个可能因素，并在精神分裂症患者中显示出改变。我们测试了全基因组亚硫酸氢盐测序是否可以用于同时定量 rDNA CN 和测量 45S rDNA 基因座的 DNA 甲基化。使用这种方法，我们观察到 rDNA CN 个体间存在高度的变异，并且在几个死后组织中个体内的拷贝差异有限。此外，我们在 16 个 ASD 与 11 个对照样本中没有观察到 ASD 大脑 rDNA CN 或 DNA 甲基化的任何显著改变。同样，在比较 28 个精神分裂症(Scz)患者与 25 个对照的神经元或 22 个 Scz 样本与 20 个对照的少突胶质细胞时，也没有检测到差异。然而，我们的分析揭示了多个组织中 45S rDNA 基因座的 CN 和 DNA 甲基化之间的强正相关。这在大脑中观察到，并在小肠、脂肪组织和胃组织中得到证实。这应该揭示了一种可能的剂量补偿机制，该机制沉默额外的 rDNA 拷贝以确保核糖体生物发生的同型调节。
