Stelzer Yonatan, Wu Hao, Song Yuelin, Shivalila Chikdu S, Markoulaki Styliani, Jaenisch Rudolf
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Cell Rep. 2016 Sep 20;16(12):3167-3180. doi: 10.1016/j.celrep.2016.08.066.
Parent-specific differentially methylated regions (DMRs) are established during gametogenesis and regulate parent-specific expression of imprinted genes. Monoallelic expression of imprinted genes is essential for development, suggesting that imprints are faithfully maintained in embryos and adults. To test this hypothesis, we targeted a reporter for genomic methylation to the imprinted Dlk1-Dio3 intergenic DMR (IG-DMR) to assess the methylation of both parental alleles at single-cell resolution. Biallelic gain or loss of IG-DMR methylation occurred in a small fraction of mouse embryonic stem cells, significantly affecting developmental potency. Mice carrying the reporter in either parental allele showed striking parent-specific changes in IG-DMR methylation, causing substantial and consistent tissue- and cell-type-dependent signatures in embryos and postnatal animals. Furthermore, dynamics in DNA methylation persisted during adult neurogenesis, resulting in inter-individual diversity. This substantial cell-cell DNA methylation heterogeneity implies that dynamic DNA methylation variations in the adult may be of functional importance.
亲本特异性差异甲基化区域（DMRs）在配子发生过程中建立，并调控印记基因的亲本特异性表达。印记基因的单等位基因表达对发育至关重要，这表明印记在胚胎和成年个体中得以忠实维持。为了验证这一假设，我们将一个基因组甲基化报告基因靶向印记的Dlk1-Dio3基因间DMR（IG-DMR），以单细胞分辨率评估两个亲本等位基因的甲基化情况。一小部分小鼠胚胎干细胞中发生了IG-DMR甲基化的双等位基因获得或缺失，显著影响发育潜能。在任一亲本等位基因中携带报告基因的小鼠在IG-DMR甲基化方面表现出显著的亲本特异性变化，在胚胎和出生后动物中导致大量且一致的组织和细胞类型依赖性特征。此外，DNA甲基化动态变化在成体神经发生过程中持续存在，导致个体间的多样性。这种显著的细胞间DNA甲基化异质性意味着成体中动态的DNA甲基化变化可能具有功能重要性。
