Son Dongmin, Kong Yifan, Tan Yulian, Hu Ting, Shi Lei, Yi Soojin V
Department of Ecology, Evolution and Marine Biology, University of California Santa Barbara.
Department of Molecular, Cellular and Developmental Biology, Neuroscience Research Institute, University of California Santa Barbara.
bioRxiv. 2024 Jun 6:2024.06.05.597676. doi: 10.1101/2024.06.05.597676.
The tree shrew () is a promising emerging model organism in biomedical studies, notably due to their evolutionary proximity to primates. To enhance our understanding of how DNA methylation is implicated in regulation of gene expression and the X chromosome inactivation (XCI) in tree shrew brains, here we present their first genome-wide, single-base-resolution methylomes integrated with transcriptomes from prefrontal cortices. We discovered both divergent and conserved features of tree shrew DNA methylation compared to that of other mammals. DNA methylation levels of promoter and gene body regions are negatively correlated with gene expression, consistent with patterns in other mammalian brains studied. Comparing DNA methylation patterns of the female and male X chromosomes, we observed a clear and significant global reduction (hypomethylation) of DNA methylation across the entire X chromosome in females. Our data suggests that the female X hypomethylation does not directly contribute to the gene silencing of the inactivated X chromosome nor does it significantly drive sex-specific gene expression of tree shrews. However, we identified a putative regulatory region in the 5' end of the X inactive specific transcript ( gene, a key gene for XCI, whose pattern of differential DNA methylation strongly relate to its differential expression between male and female tree shrews. We show that differential methylation of this region is conserved across different species. Moreover, we provide evidence suggesting that the observed difference between human and tree shrew X-linked promoter methylation is associated with the difference in genomic CpG contents. Our study offers novel information on genomic DNA methylation of tree shrews, as well as insights into the evolution of X chromosome regulation in mammals.
树鼩是生物医学研究中一种很有前景的新兴模式生物，特别是因为它们在进化上与灵长类动物相近。为了增进我们对DNA甲基化如何参与树鼩大脑中基因表达调控和X染色体失活（XCI）的理解，在此我们展示了它们首个全基因组、单碱基分辨率的甲基化组，并结合了前额叶皮质的转录组。与其他哺乳动物相比，我们发现了树鼩DNA甲基化的不同和保守特征。启动子和基因体区域的DNA甲基化水平与基因表达呈负相关，这与其他已研究的哺乳动物大脑中的模式一致。比较雌性和雄性X染色体的DNA甲基化模式，我们观察到雌性整个X染色体上的DNA甲基化明显且显著地整体减少（低甲基化）。我们的数据表明，雌性X染色体低甲基化既不直接导致失活X染色体的基因沉默，也不显著驱动树鼩的性别特异性基因表达。然而，我们在X失活特异性转录本（基因，XCI的关键基因） 的5'端鉴定出一个假定的调控区域，其DNA甲基化差异模式与雄性和雌性树鼩之间的差异表达密切相关。我们表明该区域的差异甲基化在不同物种间是保守的。此外，我们提供的证据表明，人类和树鼩X连锁启动子甲基化之间观察到 的差异与基因组CpG含量的差异有关。我们的研究提供了关于树鼩基因组DNA甲基化的新信息，以及对哺乳动物X染色体调控进化的见解。
