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.

抽象的 Fat is a vital cellular resource for both reproduction and immunity.脂质的大量可用性和特异性 ic lipid species influence fertility and immunity as they act as energy source and signaling molecules, respec- 积极地。 There is ample evidence that differential fat allocation impacts the health of both women and men.因此， lipid metabolism is inextricably linked to immunity and fertility, but the underlying molecular connections are 不太了解。 These are challenging to address in long-lived, slow-reproducing mammalian models.凯- 秀丽隐杆线虫对于研究脂质在驱动免疫-生育关系中的作用特别有价值 ship due to its high reproductive rate, and because in worms the deposition of maternal fat into oocytes can be 易于可视化、评估和操作。该提议基于我们的发现，即秀丽隐杆线虫 蛋白质 TCER-1 充当代谢开关，调节脂质水解以形成能量权衡 免疫力和生育能力之间。 我们鉴定出 TCER-1（人类转录延伸/剪接因子 TCERG1 的同源物）是一种蛋白质， promoted longevity specifically in response to reproductive signals, by establishing lipid homeostasis. TCER-1 对于生殖健康至关重要。最近，我们报道了 TCER-1 仅在 生命的生育阶段；提高其水平可以减轻感染引起的生育能力下降，这表明它可能会抑制 它具有免疫力，促进生殖健康。 In unpublished, preliminary studies, we have now discovered that TCER-1 对于脂肪在鸡蛋中的适当沉积至关重要。 Additionally, through an unbiased RNA-Seq analysis, we 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，分别在正常繁殖期间和感染时。因此， 我们假设 TCER-1 通过调节脂肪酶表达和交替作用广泛改变脂质水解 主动剪接，抑制免疫力并支持生育能力。我们建议通过探索来检验这个假设 TCER-1 调节的 DAG 和 TAG 脂肪酶影响免疫和母胎脂肪酶的机制 pid 分布。我们还将研究 TCER-1 在发育过程中如何决定母体和胚胎脂质组。 正常条件下和病原体暴露后。总的来说，这项研究将通过以下方式揭示基本机制： 确定了针对不同生理目的的脂肪分配。进一步的重大进展 通过这项工作可以实现的目标包括证明（i）脂肪水解在母胎中的核心作用 脂质分布，以及（ii）剪接作为塑造宿主病原体战斗的关键调节步骤。

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