Role of the transcription elongation and splicing factor TCER-1 in repressing immunity and promoting fertility

摘要 脂肪是生殖和免疫的重要细胞资源。脂类的批量可获得性和特定的- IC脂类物质分别作为能量来源和信号分子影响生育和免疫功能。 分别。有充分的证据表明，不同的脂肪分配对女性和男性的健康都有影响。因此， 脂肪代谢与免疫和生育有着千丝万缕的联系，但潜在的分子联系是 人们对此知之甚少。在长寿、繁殖缓慢的哺乳动物模型中解决这些问题是具有挑战性的。CAE- 雅致诺哈迪斯对研究血脂在推动免疫-生育关系中的作用特别有价值。 由于其繁殖率很高，而且因为在蠕虫体内母体脂肪可以沉积到卵母细胞中 易于可视化、评估和操纵。这一建议是基于我们的发现，线虫 蛋白质，TCER-1，作为一个代谢开关，调节脂肪水解，形成能量平衡。 青春期免疫力和生育力。 我们鉴定了人类转录延伸/剪接因子TCERG1的同源物TCER-1是一种 通过建立脂类平衡，特别是通过对生殖信号的反应来促进长寿。TCER-1 对生殖健康至关重要。最近，我们报道了TCER-1在 生命的生育阶段；提高它的水平可以缓解感染导致的生育下降，这表明它可能抑制- 它具有促进生殖健康的免疫力。在未发表的初步研究中，我们现在发现 TCER-1对卵子中脂肪的正常沉积至关重要。此外，通过无偏见的RNA-Seq分析，我们 发现TCER-1控制多种二甘油酯的选择性剪接(AS)和差异表达 (DAG)和甘油三酯(TAG)脂肪酶分别在正常生殖期间和感染时。因此， 我们推测，TCER-1通过调节脂肪酶的表达和交替，广泛地改变了脂肪的水解性。 选择性剪接，以抑制免疫力和支持生育。我们建议通过探索 TCER-1调节的DAG-和TAG-脂肪酶影响免疫和母婴免疫的机制 PID分布。我们还将研究TCER-1如何决定母体和胚胎的脂类 在正常条件下和在病原体暴露时。总体而言，本研究将通过以下方式揭示基本机制 确定哪种脂肪分配给不同的生理目的。进一步的重大进展， 可能通过这项工作实现的工作包括：(I)证明脂肪在母体-胎儿中的中心作用 脂质分布，以及(Ii)剪接作为塑造宿主-病原体战斗的关键调控步骤。

ABSTRACT Fat is a vital cellular resource for both reproduction and immunity. Both the bulk availability of lipids and specif- ic lipid species influence fertility and immunity as they act as energy source and signaling molecules, respec- tively. There is ample evidence that differential fat allocation impacts the health of both women and men. Thus, lipid metabolism is inextricably linked to immunity and fertility, but the underlying molecular connections are poorly understood. These are challenging to address in long-lived, slow-reproducing mammalian models. Cae- norhabditis elegans is especially valuable for studying the role of lipids in driving the immunity-fertility relation- ship due to its high reproductive rate, and because in worms the deposition of maternal fat into oocytes can be easily visualized, assessed and manipulated. This proposal is based on our discoveries that the C. elegans protein, TCER-1, acts as a metabolic switch that regulates lipid hydrolysis to shape the energetic trade-off be- tween immunity and fertility. We identified TCER-1, homolog of human transcription elongation/splicing factor, TCERG1, as a protein that promoted longevity specifically in response to reproductive signals, by establishing lipid homeostasis. TCER-1 is critical for reproductive fitness. Recently, we reported that TCER-1 represses immunity exclusively during the fertile stages of life; raising its level alleviates infection-induced fertility decline, suggesting that it may inhib- it immunity to promote reproductive fitness. In unpublished, preliminary studies, we have now discovered that TCER-1 is critical for proper fat deposition into eggs. Additionally, through an unbiased RNA-Seq analysis, we found that TCER-1 controls the alternative splicing (AS) and differential expression of multiple diglyceride (DAG) and triglyceride (TAG) lipases, respectively, both during normal reproduction and upon infection. Hence, we hypothesize that TCER-1 widely alters lipid hydrolysis, through regulation of lipase expression and alterna- tive splicing, to repress immunity and support fertility. We propose to test this hypothesis by exploring the mechanisms by which the DAG- and TAG-lipases regulated by TCER-1 impact immunity and maternal-fetal li- pid distribution. We will also investigate how TCER-1 dictates the maternal and embryonic lipidomes during normal conditions and upon pathogen exposure. Overall, this study will reveal fundamental mechanisms by which fat allocation towards distinct physiological purposes is determined. Further significant advances that may be achieved through this work include demonstration of (i) a central role for fat hydrolysis in maternal-fetal lipid distribution, and (ii) splicing as a key regulatory step in shaping host-pathogen combat.