Developmental regulation of neuronal gene expression by Elongator complex protein 1 dosage.
Developmental regulation of neuronal gene expression by Elongator complex protein 1 dosage.
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伸长因子复合蛋白 1 的剂量对神经元基因表达的发育调控
DOI：
10.1016/j.jgg.2021.11.011
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发表时间：
2022-07
影响因子：
5.9
通讯作者：
Slaugenhaupt, Susan A.
中科院分区：
文献类型：
--
作者：
Morini, Elisabetta;Gao, Dadi;Logan, Emily M.;Salani, Monica;Krauson, Aram J.;Chekuri, Anil;Chen, Yei-Tsung;Ragavendran, Ashok;Chakravarty, Probir;Erdin, Serkan;Stortchevoi, Alexei;Svejstrup, Jesper Q.;Talkowski, Michael E.;Slaugenhaupt, Susan A.
家族性自主神经功能障碍（FD）是一种遗传性感觉和自主神经病变，由Elongator complex protein 1（ELP 1）基因突变引起，该突变导致ELP 1蛋白的组织特异性减少。我们的工作，以产生一个表型小鼠模型FD为首的发现，纯合子删除小鼠Elp 1基因导致胚胎死亡之前，中期妊娠。鉴于FD是由ELP 1的减少而不是丢失引起的，我们通过将不同拷贝数的人FD ELP 1转基因引入Elp 1敲除小鼠（Elp 1-/-）中产生了两种新的小鼠模型，并观察到人ELP 1表达以剂量依赖性方式挽救胚胎发育。然后，我们在小鼠胚胎中进行了全面的转录组分析，以确定其表达与ELP 1的量相关的基因和途径。我们发现，ELP 1对负责神经系统发育的基因的表达至关重要。此外，差异表达基因的基因长度分析表明，Elp 1的缺失主要影响长基因的表达，并且通过逐渐恢复Elongator，它们的表达被逐渐挽救。最后，通过评估共表达模块，我们确定了依赖于ELP 1表达的独特表达模式的基因集。
Familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy, is caused by a mutation in the Elongator complex protein 1 (ELP1) gene that lead to a tissue-specific reduction of ELP1 protein. Our work to generate a phenotypic mouse model for FD headed to the discovery that homozygous deletion of the mouse Elp1 gene leads to embryonic lethality prior to mid-gestation. Given that FD is caused by a reduction, not loss, of ELP1, we generated two new mouse models by introducing different copy numbers of the human FD ELP1 transgene into the Elp1 knockout mouse (Elp1−/−) and observed that human ELP1 expression rescues embryonic development in a dose dependent manner. We then conducted a comprehensive transcriptome analysis in mouse embryos to identify genes and pathways whose expression correlates with the amount of ELP1. We found that ELP1 is essential for the expression of genes responsible for nervous system development. Further, gene length analysis of the differentially expressed genes showed that the loss of Elp1 mainly impacts the expression of long genes and that by gradually restoring Elongator their expression is progressively rescued. Finally, through evaluation of co-expression modules, we identified gene sets with unique expression patterns that depended on ELP1 expression.
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影响因子：
3.7
作者：
Li F;Ma J;Ma Y;Hu Y;Tian S;White RE;Han G
通讯作者：
Han G
影响因子：
3.9
作者：
Addis, Laura;Ahn, Joo Wook;Pal, Deb K.
通讯作者：
Pal, Deb K.
影响因子：
4.3
作者：
Bauer, Fanelie;Hermand, Damien
通讯作者：
Hermand, Damien
DOI：
10.1073/pnas.1308596110
发表时间：
2013-11-12
影响因子：
11.1
作者：
George, Lynn;Chaverra, Marta;Lefcort, Frances
通讯作者：
Lefcort, Frances
影响因子：
1.8
作者：
Constantine, Ryan;Zhang, Houbin;Gerstner, Cecilia D.;Frederick, Jeanne M.;Baehr, Wolfgang
通讯作者：
Baehr, Wolfgang