Dunaway Keith, Goorha Sarita, Matelski Lauren, Urraca Nora, Lein Pamela J, Korf Ian, Reiter Lawrence T, LaSalle Janine M
Medical Microbiology and Immunology, UC Davis, Davis, California, USA.
Genome Center, UC Davis, Davis, California, USA.
Stem Cells. 2017 Apr;35(4):981-988. doi: 10.1002/stem.2563. Epub 2017 Jan 19.
Early embryonic stages of pluripotency are modeled for epigenomic studies primarily with human embryonic stem cells (ESC) or induced pluripotent stem cells (iPSCs). For analysis of DNA methylation however, ESCs and iPSCs do not accurately reflect the DNA methylation levels found in preimplantation embryos. Whole genome bisulfite sequencing (WGBS) approaches have revealed the presence of large partially methylated domains (PMDs) covering 30%-40% of the genome in oocytes, preimplantation embryos, and placenta. In contrast, ESCs and iPSCs show abnormally high levels of DNA methylation compared to inner cell mass (ICM) or placenta. Here we show that dental pulp stem cells (DPSCs), derived from baby teeth and cultured in serum-containing media, have PMDs and mimic the ICM and placental methylome more closely than iPSCs and ESCs. By principal component analysis, DPSC methylation patterns were more similar to two other neural stem cell types of human derivation (EPI-NCSC and LUHMES) and placenta than were iPSCs, ESCs or other human cell lines (SH-SY5Y, B lymphoblast, IMR90). To test the suitability of DPSCs in modeling epigenetic differences associated with disease, we compared methylation patterns of DPSCs derived from children with chromosome 15q11.2-q13.3 maternal duplication (Dup15q) to controls. Differential methylation region (DMR) analyses revealed the expected Dup15q hypermethylation at the imprinting control region, as well as hypomethylation over SNORD116, and novel DMRs over 147 genes, including several autism candidate genes. Together these data suggest that DPSCs are a useful model for epigenomic and functional studies of human neurodevelopmental disorders. Stem Cells 2017;35:981-988.
多能性的早期胚胎阶段主要通过人类胚胎干细胞（ESC）或诱导多能干细胞（iPSC）进行表观基因组学研究建模。然而，对于DNA甲基化分析，ESC和iPSC并不能准确反映植入前胚胎中的DNA甲基化水平。全基因组亚硫酸氢盐测序（WGBS）方法揭示，在卵母细胞、植入前胚胎和胎盘中存在覆盖基因组30%-40%的大片部分甲基化区域（PMD）。相比之下，与内细胞团（ICM）或胎盘相比，ESC和iPSC显示出异常高水平的DNA甲基化。在这里，我们表明，源自乳牙并在含血清培养基中培养的牙髓干细胞（DPSC）具有PMD，并且比iPSC和ESC更接近地模拟ICM和胎盘甲基化组。通过主成分分析，与iPSC、ESC或其他人类细胞系（SH-SY5Y、B淋巴细胞母细胞、IMR90）相比，DPSC甲基化模式与另外两种人类来源的神经干细胞类型（EPI-NCSC和LUHMES）以及胎盘更相似。为了测试DPSC在模拟与疾病相关的表观遗传差异方面的适用性，我们比较了来自患有15号染色体q11.2-q13.3母系重复（Dup15q）的儿童的DPSC与对照组的甲基化模式。差异甲基化区域（DMR）分析揭示了在印记控制区域预期的Dup15q高甲基化，以及SNORD116上的低甲基化，以及超过147个基因上的新型DMR，包括几个自闭症候选基因。这些数据共同表明，DPSC是人类神经发育障碍表观基因组学和功能研究的有用模型。《干细胞》2017年；35:981-988。
