İzmir Biomedicine and Genome Center (IBG), 35340, İnciraltı, İzmir, Turkey.
Department of Genetics and Bioengineering, İzmir University of Economics, Faculty of Engineering, 35330, Balçova, İzmir, Turkey.
BMC Genomics. 2019 May 31;20(1):439. doi: 10.1186/s12864-019-5803-1.
The last decade witnessed a number of genome-wide studies on human pre-implantation, which mostly focused on genes and provided only limited information on repeats, excluding the satellites. Considering the fact that repeats constitute a large portion of our genome with reported links to human physiology and disease, a thorough understanding of their spatiotemporal regulation during human embryogenesis will give invaluable clues on chromatin dynamics across time and space. Therefore, we performed a detailed expression analysis of all repetitive DNA elements including the satellites across stages of human pre-implantation and embryonic stem cells.
We uncovered stage-specific expressions of more than a thousand repeat elements whose expressions fluctuated with a mild global decrease at the blastocyst stage. Most satellites were highly expressed at the 4-cell level and expressions of ACRO1 and D20S16 specifically peaked at this point. Whereas all members of the SVA elements were highly upregulated at 8-cell and morula stages, other transposons and small RNA repeats exhibited a high level of variation among their specific subtypes. Our repeat enrichment analysis in gene promoters coupled with expression correlations highlighted potential links between repeat expressions and nearby genes, emphasising mostly 8-cell and morula specific genes together with SVA_D, LTR5_Hs and LTR70 transposons. The DNA methylation analysis further complemented the understanding on the mechanistic aspects of the repeatome's regulation per se and revealed critical stages where DNA methylation levels are negatively correlating with repeat expression.
Taken together, our study shows that specific expression patterns are not exclusive to genes and long non-coding RNAs but the repeatome also exhibits an intriguingly dynamic pattern at the global scale. Repeats identified in this study; particularly satellites, which were historically associated with heterochromatin, and those with potential links to nearby gene expression provide valuable insights into the understanding of key events in genomic regulation and warrant further research in epigenetics, genomics and developmental biology.
过去十年见证了大量针对人类着床前基因组范围的研究，这些研究主要集中在基因上，仅提供了有关重复序列的有限信息，排除了卫星序列。考虑到重复序列构成了我们基因组的很大一部分，并且与人类生理学和疾病有关，因此深入了解它们在人类胚胎发生过程中的时空调控将为跨时间和空间的染色质动力学提供宝贵线索。因此，我们对人类着床前和胚胎干细胞各个阶段的所有重复 DNA 元件（包括卫星序列）进行了详细的表达分析。
我们揭示了超过一千个重复元件的阶段特异性表达，其表达随着囊胚阶段的轻微全局下降而波动。大多数卫星序列在 4 细胞水平高度表达，而 ACRO1 和 D20S16 的表达则在该阶段达到峰值。虽然 SVA 元件的所有成员在 8 细胞和桑椹胚阶段高度上调，但其他转座子和小 RNA 重复序列在其特定亚型中表现出高度变化。我们在基因启动子中的重复富集分析与表达相关性相结合，突出了重复表达与附近基因之间的潜在联系，强调了主要是 8 细胞和桑椹胚特异性基因以及 SVA_D、LTR5_Hs 和 LTR70 转座子。DNA 甲基化分析进一步补充了对重复序列调控本身的机制方面的理解，并揭示了 DNA 甲基化水平与重复表达呈负相关的关键阶段。
综上所述，我们的研究表明，特定的表达模式不仅限于基因和长非编码 RNA，重复序列在全局范围内也表现出引人入胜的动态模式。本研究中鉴定的重复序列；特别是卫星序列，它们历史上与异染色质有关，以及那些与附近基因表达有潜在联系的重复序列，为理解基因组调控中的关键事件提供了有价值的见解，并值得在表观遗传学、基因组学和发育生物学领域进一步研究。
