Characterizing the genetic and epigenetic determinants of multicellularity

表征多细胞性的遗传和表观遗传决定因素

• 批准号: 2326672
• 负责人: Eric Greer
• 金额: $ 120万
• 依托单位: Washington University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2326672&HistoricalAwards=false
• 关键词: Characterizing; genetic; epigenetic; determinants; multicellularity

How did multicellularity arise? This is a fundamental question as life began as single celled organisms, then branched into various multicellular lineages. When cells began to cooperate with each other to establish the multicellular state, several key features co-evolved; cell adherence, intercellular communication, cellular specialization in adopting unique functions for the survival of the whole organism, along with altruism (i.e., a state where a cell would not only care about its own survival but even be willing to sacrifice itself for the survival of the organism). Understanding these basic features is important for understanding basic evolution. A suite of genes has been identified that may provide clues to the origins of multicellularity and this project will investigate these genes (and their regulation) for their contribution to the multicellular state. The Broader Impacts of the work include the intrinsic merit as multicellularity is a feature of much life on the planet (including humans). Moreover, it is also important as many of these very processes go awry when specific diseases develop. In cancer, for example, a cell will no longer localizes to the tissue where it is supposed to grow and no longer functions in a manner that is beneficial for the overall survival of the organism but will instead adopt a selfish fate where it only cares about its own survival. Additional activities include the training of undergraduate and graduate students, along with post-doctoral fellows in a breadth of research methodologies at two institutions. To decipher how evolution transitioned from unicellular to multicellular states, we propose leveraging one of the rare organisms that adopts and regularly transits both unicellular and multicellular states. Dictyostelium discodeum undergoes dramatic physiological changes when food is scarce, transforming from a single celled amoeba to a multicellular fruiting body while maintaining the same genetic code. We have hypothesized that epigenetic changes help to drive this transition from unicellular to multicellular fates. We recently published work identifying genes whose expression and epigenomic signatures were different between the unicellular and multicellular state suggesting that they might play important roles in regulating the transition to multicellularity. We found that by deleting or overexpressing these genes, they are both necessary and sufficient for multicellularity in Dictyostelium. Here, we propose to extend these initial findings by using state of the art technologies to characterize at single-cell resolution the epigenetic and transcriptional alterations that occur in Dictyostelium as it transitions between unicellular and multicellular states. In parallel, we will investigate the transcriptional and epigenetic mechanisms underlying cellular altruism, an essential characteristic of multicellular organisms. These experiments will provide fundamental insight into the genetic and epigenetic mechanisms underlying the transition from uni to multicellularity.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

多细胞性是如何产生的？ 这是一个基本问题，因为生命始于单细胞生物，然后分支成各种多细胞谱系。 当细胞开始相互合作建立多细胞状态时，几个关键特征共同进化；细胞粘附、细胞间通讯、为整个生物体的生存而采取独特功能的细胞专门化，以及利他主义（即细胞不仅关心自己的生存，甚至愿意为了生物体的生存而牺牲自己的状态）。了解这些基本特征对于理解基本进化非常重要。 已经鉴定出一组基因可能为多细胞起源提供线索，该项目将研究这些基因（及其调控）对多细胞状态的贡献。 这项工作的更广泛影响包括其内在优点，因为多细胞性是地球上许多生命（包括人类）的一个特征。 此外，这一点也很重要，因为当特定疾病发生时，许多这些过程都会出错。例如，在癌症中，细胞将不再定位于它应该生长的组织，也不再以有利于生物体整体生存的方式发挥作用，而是采取自私的命运，只关心自己的生存。 其他活动包括在两个机构对本科生和研究生以及博士后进行广泛研究方法的培训。 为了破译进化如何从单细胞状态转变为多细胞状态，我们建议利用一种采用并定期转变单细胞和多细胞状态的稀有生物体。当食物匮乏时，盘基网柄菌会经历剧烈的生理变化，从单细胞变形虫转变为多细胞子实体，同时保持相同的遗传密码。我们假设表观遗传变化有助于推动从单细胞命运到多细胞命运的转变。我们最近发表的工作鉴定了在单细胞和多细胞状态下表达和表观基因组特征不同的基因，表明它们可能在调节向多细胞状态的转变中发挥重要作用。我们发现，通过删除或过度表达这些基因，它们对于盘基网柄菌的多细胞性来说既是必要的也是充分的。在这里，我们建议通过使用最先进的技术来扩展这些初步发现，以单细胞分辨率表征盘基网柄菌在单细胞和多细胞状态之间转变时发生的表观遗传和转录改变。与此同时，我们将研究细胞利他主义背后的转录和表观遗传机制，这是多细胞生物的基本特征。这些实验将为从单细胞向多细胞转变背后的遗传和表观遗传机制提供基本见解。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。