Characterizing the genetic and epigenetic determinants of multicellularity

多细胞生物是如何产生的？ 这是一个基本的问题，因为生命起源于单细胞生物，然后分支成各种多细胞谱系。 当细胞开始相互合作以建立多细胞状态时，几个关键特征共同进化;细胞粘附，细胞间通讯，细胞特化以采用独特功能来维持整个生物体的生存，沿着利他主义（即，一个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。 已经确定了一组基因，可能为多细胞起源提供线索，本项目将研究这些基因（及其调控）对多细胞状态的贡献。 这项工作的更广泛的影响包括内在的优点，因为多细胞性是地球上许多生命（包括人类）的特征。 此外，这也很重要，因为当特定疾病发展时，许多这些过程都会出错。例如，在癌症中，细胞将不再局限于它应该生长的组织，并且不再以有利于有机体整体生存的方式发挥作用，而是采取自私的命运，它只关心自己的生存。 其他活动包括在两个机构培训本科生和研究生，沿着还有博士后研究员，学习广泛的研究方法。 为了破译进化如何从单细胞状态过渡到多细胞状态，我们建议利用一种罕见的生物，它采用并定期转换单细胞和多细胞状态。当食物缺乏时，盘基网柄藻会发生剧烈的生理变化，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这种从单细胞到多细胞命运的转变。我们最近发表的工作，确定基因的表达和表观基因组签名是不同的单细胞和多细胞状态之间，这表明他们可能在调节过渡到多细胞的重要作用。我们发现，通过删除或过表达这些基因，它们是必要的和足够的多细胞在网骨藻。在这里，我们建议通过使用最先进的技术来扩展这些初步的研究结果，以表征在单细胞分辨率的表观遗传和转录的改变，发生在Dictyosteoblasts，因为它之间的单细胞和多细胞状态的过渡。与此同时，我们将研究细胞利他主义的转录和表观遗传机制，这是多细胞生物的一个基本特征。这些实验将为从单细胞到多细胞的转变提供基本的遗传和表观遗传机制。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值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.