The role of post-transcriptional regulation in feeding behaviour and metabolism

转录后调控在摄食行为和代谢中的作用

• 批准号: RGPIN-2022-04441
• 负责人: Anreiter, Ina
• 金额: $ 2.26万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=744893
• 关键词: role; post; transcriptional; regulation; feeding

Feeding behaviour is a complex phenotype with a high degree of plasticity. Changes in the nutritional environment affect food-search behaviour, food consumption, and metabolic phenotypes. Thus, genes that modulate feeding behaviour and metabolism are often plastically regulated. Furthermore, genes that regulate behavioural phenotypes are often pleiotropic, exercising multiple independent food-related functions through multiple gene products as well as time and tissue specific expression patterns. My previous research has focused on mapping the functions of one such plastic and pleiotropic gene, the foraging (for) gene. I showed that at the transcriptional level, expression of the different for gene products is affected by genetic variability in for's promoters and by epigenetic modifications. In addition to transcriptional regulation, post-transcriptional regulators can play an important role in regulating gene expression. In the context of plastically expressed genes specifically, post-transcriptional regulators might be crucial as they allow gene expression to change on short timescales. However, very little is known about the role post-transcriptional mechanisms play in regulating the expression of genes with plastic and pleiotropic behavioural functions. My long-term research program focuses on understanding the transcriptional and post-transcriptional regulatory processes that underlie feeding behaviour and food-related phenotypes. Towards this goal, this proposal focuses on investigating two post-transcriptional gene regulatory mechanisms that have not been investigated in the context of feeding behaviour. This includes post-transcriptional regulation by RNA-binding proteins (aim 1), and post-transcriptional regulation by mRNA epigenetic modifications (epitranscriptomic marks; aim 2 and 3). Although mRNA-binding proteins are known to regulate gene expression, their function in the context of behaviour is not well understood. Furthermore, the epigenetic landscape on DNA is emerging as an exciting interconnected system that shapes the effects of environment on development and behaviour. This proposal presents the first steps towards understanding if the epigenetic landscape on mRNA exercises a similar function. This proposal approaches the above questions with two mechanistic aims investigating the role of port-transcriptional regulation in expression of a well-known modulator of food-related phenotypes, the for gene: Aim1 - Determine the role of Pumilio in regulating for gene expression, feeding behaviour and metabolism and Aim2 - Determine the role of the epitranscriptomic mark m6A in regulating for gene expression, feeding behaviour, and metabolism. The last aim of this proposal seeks to establish a broad foundation for additional genes and pathways that are epitranscriptomically regulated to affect feeding behaviour: Aim 3 - Identify genes and pathways which are epitranscriptomically modified to regulate feeding behaviour and metabolism.

摄食行为是一种具有高度可塑性的复杂表型。营养环境的变化会影响觅食行为、食物消费和代谢表型。因此，调节摄食行为和新陈代谢的基因通常是可塑性调节的。此外，调节行为表型的基因通常是多效性的，通过多个基因产物以及特定于时间和组织的表达模式行使多种独立的与食物相关的功能。我之前的研究重点是定位这样一个塑料和多效性基因的功能，即觅食(For)基因。我的研究表明，在转录水平上，不同的for基因产物的表达受到for启动子的遗传变异和表观遗传修饰的影响。除了转录调控外，转录后调控因子在基因表达调控中也发挥着重要作用。在特定的塑料表达基因的背景下，转录后调控可能是至关重要的，因为它们允许基因表达在短时间尺度上发生变化。然而，人们对转录后机制在调节具有可塑性和多效性行为功能的基因表达中所起的作用知之甚少。我的长期研究计划侧重于了解构成摄食行为和与食物相关的表型的转录和转录后调控过程。为了实现这一目标，本提案侧重于研究两种转录后基因调控机制，这两种机制尚未在摄食行为的背景下进行研究。这包括RNA结合蛋白的转录后调节(目标1)，以及信使核糖核酸表观遗传修饰的转录后调节(表位转录标记；目标2和3)。尽管已知信使核糖核酸结合蛋白可以调节基因表达，但它们在行为背景下的功能还不是很清楚。此外，DNA上的表观遗传景观正在成为一个令人兴奋的相互关联的系统，它塑造了环境对发育和行为的影响。这一建议是理解mRNA上的表观遗传景观是否发挥类似功能的第一步。这项提案探讨上述问题的两个机制目的是研究端口转录调控在众所周知的食物相关表型调节因子For基因表达中的作用：Aim1-确定Pumilio在基因表达、取食行为和代谢调节中的作用和AIM2-确定表位转录标记M6A在基因表达、取食行为和代谢调节中的作用。该提案的最后一个目的是为更多的基因和途径奠定广泛的基础，这些基因和途径受到表观转录调控，以影响取食行为：目标3--识别表位修饰的基因和途径，以调节取食行为和代谢。