Vitamin C activates young LINE-1 elements in mouse embryonic stem cells via H3K9me3 demethylation
Vitamin C activates young LINE-1 elements in mouse embryonic stem cells via H3K9me3 demethylation
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维生素 C 通过 H3K9me3 去甲基化激活小鼠胚胎干细胞中年轻的 LINE-1 元件
DOI：
10.1101/2023.08.07.552254
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Cheng K
中科院分区：
文献类型：
--
作者：
Cheng K
维生素C(VitC)可增强依赖于2-氧戊二酸的双加氧酶的活性，包括催化DNA去甲基化的Tet酶和Jumonji结构域的组蛋白去甲基酶。由VitC促进的表观遗传学重塑提高了诱导多能干细胞来源的效率，并需要在胚胎干细胞(ESCs)中达到接近模拟早期胚泡内细胞团的多潜能基态。然而，全基因组DNA和组蛋白去甲基化可以导致转座元件(TES)的上调，而在培养液中添加维生素C如何影响多能干细胞中转座元件的表达尚不清楚。结果显示，在小鼠ESCs中，VitC增加了几个TE家族的表达，包括进化上年轻的LINE-1(L1)元件。我们发现，Tet活性对于L1的上调是必不可少的，相反，它的发生主要是由于KDM4A/C组蛋白去甲基酶介导的H3K9me3丢失。尽管L1水平增加，但我们没有检测到维生素C处理细胞的体细胞插入率增加。值得注意的是，用VitC处理人ESCs也增加了L1蛋白的水平，尽管是通过不同的转录后机制。结论VitC通过表观遗传机制直接调节小鼠L1s和其他TES的表达，潜在的下游效应与L1s在细胞功能中的多个新兴角色有关。
BackgroundVitamin 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.ResultsHere 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.ConclusionVitC 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.
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影响因子：
3.5
作者：
S. Wissing;M. Muñoz-Lopez;Angela Macia;Zhiyuan Yang;M. Montaño;William O. Collins;J. García-Pérez;J. V. Moran;W. Greene
通讯作者：
S. Wissing;M. Muñoz-Lopez;Angela Macia;Zhiyuan Yang;M. Montaño;William O. Collins;J. García-Pérez;J. V. Moran;W. Greene
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
16.6
作者：
Klawitter S;Fuchs NV;Upton KR;Muñoz-Lopez M;Shukla R;Wang J;Garcia-Cañadas M;Lopez-Ruiz C;Gerhardt DJ;Sebe A;Grabundzija I;Merkert S;Gerdes P;Pulgarin JA;Bock A;Held U;Witthuhn A;Haase A;Sarkadi B;Löwer J;Wolvetang EJ;Martin U;Ivics Z;Izsvák Z;Garcia-Perez JL;Faulkner GJ;Schumann GG
通讯作者：
Schumann GG
DOI：
10.1007/978-1-4939-3372-3_24
发表时间：
2016-01-01
期刊：
TRANSPOSONS AND RETROTRANSPOSONS
影响因子：
--
作者：
de la Rica, Lorenzo;Stanley, Jatinder S.;Branco, Miguel R.
通讯作者：
Branco, Miguel R.
影响因子：
64.5
作者：
Takahashi, Kazutoshi;Yamanaka, Shinya
通讯作者：
Yamanaka, Shinya