Transcriptional and Epigenetic Control of Totipotency and Early Development by Zfp281

Columbia University Health Sciences, New York NY

Investigators

Abstract

PROJECT SUMMARY This grant proposal seeks renewal for R01 project under the title "Transcriptional and Epigenetic Control of Totipotency and Early Development by Zfp281", building on the outcomes of the previously funded and completed R01GM129157. The project centers on investigating the pivotal roles of Zfp281, a Krüppel-like zinc finger transcription factor (TF), in the transcriptional and epigenetic regulation of totipotency and zygotic genome activation (ZGA) during the early stages of mammalian development. The significance of maternal factors during the maternal-to-zygotic transition (MZT) is well-documented, with ZGA marking a critical phase where the paternal and maternal genomes undergo extensive epigenetic remodeling to acquire totipotency. Despite advancements, a comprehensive understanding of the factors and mechanisms governing ZGA and totipotency remains elusive. The challenges in modeling totipotency in vitro underline the complexity of early embryonic development and spotlight the need for further research. In the preceding grant period, substantial progress was made in delineating the functions of Zfp281 in regulating pluripotency, pluripotent state transitions, and peri-/post-implantation development using innovative mouse and cellular models. Emerging data implicates Zfp281 in controlling totipotency and ZGA, revealing its inhibitory role on the transition from pluripotent embryonic stem cells to totipotent 2-cell-like cells (2CLCs), despite its expression in both cell states. Additionally, Zfp281's expression in oocytes and cleavage-stage embryos and its critical role in early embryonic development were highlighted. These findings form the groundwork for the current renewal project, which aims to explore Zfp281's previously unrecognized roles in ZGA and totipotency regulation during cleavage-stage embryonic development. The project proposes two specific aims: 1) to define the roles and mechanisms of Zfp281 in totipotency and ZGA regulation in vitro, utilizing 2CLCs as a model system; and 2) to elucidate the roles and mechanisms of Zfp281 in totipotency and ZGA regulation in vivo, focusing on maternal and zygotic Zfp281 knockout mouse models. These aims are designed to bridge critical knowledge gaps in early mammalian development, specifically in understanding how ZGA is regulated and how early cell fates are determined. The significance of this research lies in its potential to enhance our understanding of totipotency, ZGA, and early cell fate determination, thereby contributing to advancements in regenerative medicine and the treatment of developmental disorders. The project's innovative approach stems from its focus on Zfp281 as a novel maternal factor in ZGA regulation and its potential roles in controlling the earliest cell fate decisions in development. Building on the solid foundation of preliminary data and the technical advancements made during the previous funding period, this renewal project promises to unveil novel insights into the transcriptional and epigenetic control of early embryonic development by Zfp281.