Characterizing the genetic and epigenetic determinants of multicellularity

Washington University, Saint Louis MO

Investigators

Abstract

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.