Characterizing the genetic and epigenetic determinants of multicellularity

多细胞现象是如何产生的？这是一个根本性的问题，因为生命最初是单细胞有机体，然后分支成各种多细胞谱系。当细胞开始相互合作以建立多细胞状态时，几个关键特征共同进化：细胞粘附性、细胞间通信、为整个有机体的生存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，甚至愿意为了有机体的生存而牺牲自己的状态)。理解这些基本特征对于理解基本进化很重要。已经确定了一套可能为多细胞起源提供线索的基因，该项目将研究这些基因(及其调节)对多细胞状态的贡献。这项工作的更广泛影响包括其内在价值，因为多细胞是地球上许多生命(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，这些过程中的许多都会出错。例如，在癌症中，细胞将不再局限于它应该生长的组织，不再以有利于有机体整体生存的方式发挥功能，而是采取一种自私的命运，它只关心自己的生存。其他活动包括在两个机构对本科生和研究生以及博士后研究员进行广泛的研究方法培训。为了破译进化是如何从单细胞状态转变为多细胞状态的，我们建议利用一种罕见的生物，它同时采用并定期转换单细胞和多细胞状态。在食物匮乏的情况下，盘基网眼藻经历了戏剧性的生理变化，在保持相同遗传密码的情况下，从单细胞阿米巴转变为多细胞子实体。我们假设，表观遗传变化有助于推动这种从单细胞命运向多细胞命运的转变。我们最近发表的工作确定了在单细胞和多细胞状态下其表达和表观基因组特征不同的基因，这表明它们可能在调节向多细胞转变的过程中发挥重要作用。我们发现，通过删除或过度表达这些基因，它们对网柄苔藓的多细胞特性既是必要的，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Dictyostelius在单细胞和多细胞状态之间转换时发生的表观遗传和转录变化。同时，我们将研究细胞利他主义的转录和表观遗传机制，这是多细胞生物体的基本特征。这些实验将从根本上洞察从单一细胞到多细胞的遗传和表观遗传机制。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.