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BACKGROUND

Vitamin C (vitC) enhances the activity of 2-oxoglutarate-dependent dioxygenases, including TET enzymes, which catalyse DNA demethylation, and Jumonji-domain histone demethylases. The epigenetic remodelling promoted by vitC improves the efficiency of induced pluripotent stem cell derivation, and is required to attain a ground-state of pluripotency in embryonic stem cells (ESCs) that closely mimics the inner cell mass of the early blastocyst. However, genome-wide DNA and histone demethylation can lead to upregulation of transposable elements (TEs), and it is not known how vitC addition in culture media affects TE expression in pluripotent stem cells.

RESULTS

Here we show that vitC increases the expression of several TE families, including evolutionarily young LINE-1 (L1) elements, in mouse ESCs. We find that TET activity is dispensable for L1 upregulation, and that instead it occurs largely as a result of H3K9me3 loss mediated by KDM4A/C histone demethylases. Despite increased L1 levels, we did not detect increased somatic insertion rates in vitC-treated cells. Notably, treatment of human ESCs with vitC also increases L1 protein levels, albeit through a distinct, post-transcriptional mechanism.

CONCLUSION

VitC directly modulates the expression of mouse L1s and other TEs through epigenetic mechanisms, with potential for downstream effects related to the multiple emerging roles of L1s in cellular function.

BACKGROUND

RESULTS

CONCLUSION

背景

维生素 C（vitC）增强了 2-氧戊二酸依赖性双加氧酶的活性，包括 TET 酶，其催化 DNA 去甲基化和组蛋白 Jumonji 结构域去甲基化。vitC 促进的表观遗传重塑提高了诱导多能干细胞（iPSC）的衍生效率，并且是在胚胎干细胞（ESC）中达到类似于早期囊胚内细胞团的多能性“基础状态”所必需的。然而，全基因组 DNA 和组蛋白去甲基化可能导致转座元件（TEs）的上调，并且尚不清楚培养基中添加 vitC 如何影响多能干细胞中的 TE 表达。

结果

在这里，我们表明 vitC 增加了几种 TE 家族的表达，包括进化上年轻的 LINE-1（L1）元件，在小鼠 ESC 中。我们发现 TET 活性对于 L1 的上调是可有可无的，而主要是由于 KDM4A/C 组蛋白去甲基酶介导的 H3K9me3 丢失所致。尽管 L1 水平增加，但我们没有检测到 vitC 处理的细胞中体细胞插入率增加。值得注意的是，vitC 处理人类 ESC 也增加了 L1 蛋白水平，尽管通过不同的转录后机制。