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

转录延伸和剪接因子TCER-1在抑制免疫和促进生育力中的作用

• 批准号: 10358251
• 负责人: Arjumand Ghazi
• 金额: $ 32.08万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10358251
• 关键词: 2-arachidonylglycerol; Address; Adult; Alternative Splicing; Animals; Arachidonic Acids; Automobile Driving; Biogenesis; Caenorhabditis elegans; Cells; Complex; Data; Deposition; Diglycerides; Disease; Dyes; Embryo; Endocannabinoids; Energy-Generating Resources; Enzymes; Exclusion; Exhibits; Exons; Family; Fatty acid glycerol esters; Fertility; Genes; Health; Homeostasis; Homologous Gene; Human; Hydrolysis; Immune response; Immunity; Individual; Infection; Intestines; Label; Life; Link; Lipase; Lipids; Longevity; Mediating; Metabolic; Modeling; Molecular; Molecular Genetics; Natural Immunity; Nematoda; Oils; Oocytes; Organism; Pathogenesis; Physiological; Predisposition; Process; Production; Prostaglandins; Protein Isoforms; Proteins; Public Health; RNA Splicing; Regulation; Reporting; Reproduction; Reproductive Health; Research; Resources; Role; Shapes; Signal Transduction; Signaling Molecule; Testing; Transcription Elongation; Triglycerides; Tweens; Woman; Work; base; branched chain fatty acid; combat; differential expression; egg; fetal; lipid metabolism; lipidome; lipidomics; lipoprotein lipase; member; men; metabolomics; mutant; overexpression; pathogen; pathogen exposure; reproductive; reproductive fitness; reproductive outcome; reproductive senescence; response; transcriptome sequencing

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.

摘要 脂肪是生殖和免疫的重要细胞资源。无论是大量的脂质和特定的可用性- IC脂质种类影响生育力和免疫力，因为它们分别作为能量来源和信号分子， 很好有充分的证据表明，不同的脂肪分配会影响女性和男性的健康。因此，在本发明中， 脂质代谢与免疫力和生育力密不可分，但潜在的分子联系是 不太了解。这些都是具有挑战性的，以解决在长寿，繁殖缓慢的哺乳动物模型。Cae- 秀丽小杆线虫对于研究脂质在驱动免疫力-生育力关系中的作用特别有价值- 船由于其高繁殖率，并因为在蠕虫的沉积母体脂肪进入卵母细胞， 易于可视化、评估和操作。这一建议是基于我们的发现，即C。elegans 蛋白质TCER-1作为一种代谢开关，调节脂质水解，形成能量平衡， 免疫力和生育力之间的关系。 我们鉴定了TCER-1，人类转录延伸/剪接因子TCERG 1的同源物，作为一种蛋白质， 通过建立脂质体内平衡，特别是对生殖信号的反应，促进了长寿。TCER-1 对生殖健康至关重要最近，我们报道了TCER-1仅在免疫过程中抑制免疫。 生命的可育阶段;提高其水平会导致感染引起的生育能力下降，这表明它可能会抑制- 它能增强免疫力，促进生殖健康。在未发表的初步研究中，我们发现， TCER-1对于脂肪在鸡蛋中的适当沉积至关重要。此外，通过无偏的RNA-Seq分析，我们 发现TCER-1控制多种甘油二酯的选择性剪接（AS）和差异表达， (DAG)和甘油三酯（TAG）脂肪酶。因此，我们认为， 我们假设TCER-1通过调节脂肪酶的表达和交替的蛋白质表达，广泛地改变脂质水解。 活性剪接，抑制免疫力和支持生育能力。我们建议通过探索 由TCER-1调节的DAG-和TAG-脂肪酶影响免疫和母胎利- pid分布我们还将研究TCER-1如何决定母体和胚胎的脂质体， 正常条件下和病原体暴露后。总的来说，这项研究将揭示基本机制， 确定用于不同生理目的的脂肪分配。进一步的重大进展， 可以实现通过这项工作，包括示范（i）的核心作用，脂肪水解在母胎 脂质分布，和（ii）剪接作为一个关键的监管步骤，在塑造主机病原体的战斗。

项目成果

Caenorhabditis elegans processes sensory information to choose between freeloading and self-defense strategies

秀丽隐杆线虫处理感官信息以在贪图便宜和自卫策略之间做出选择

• DOI: 10.7554/elife.56186
• 发表时间: 2020
• 期刊: eLife
• 影响因子: 7.7
• 作者: Schiffer, Jodie A;Servello, Francesco A;Heath, William R;Amrit, Francis Raj;Stumbur, Stephanie V;Eder, Matthias;Martin, Olivier MF;Johnsen, Sean B;Stanley, Julian A;Tam, Hannah
• 通讯作者: Tam, Hannah