Post-Transcriptional Regulatory Mechanisms in the Control of Cell Identity

Abstract

Cell identity is shaped by complex gene expression programs, at the core of which lies the set of messenger RNAs (mRNAs) expressed in a given cell. While there is considerable knowledge about the involvement of mRNA transcription in cell fate control, the role of post-transcriptional mechanisms – which are governed by various RNA-binding proteins (RBPs) – is less well understood. By focusing on specific RBPs, the stem cell factor LIN28 and the terminal uridylyltransferases (TUTases) ZCCHC6/11, this dissertation explores novel post-transcriptional regulatory mechanisms that contribute to the control of cell identity. Chapter 2 addresses the question of how signaling and post-transcriptional regulation are integrated to influence cell fate. In particular, we investigated the role of LIN28 phosphorylation in pluripotent stem cells (PSCs). We found that MAPK/ERK, a central signaling regulator of pluripotency, phosphorylates LIN28 to increase its protein stability and thereby enhance LIN28’s translational regulation of its mRNA targets, which contributes to the control of pluripotency transitions. These findings establish a novel link between extracellular cues, mRNA translation, and cell fate regulation. Chapter 3 examines the role of ZCCHC6/11-mediated mRNA uridylation, a recently appreciated mechanism for promoting global mRNA decay, in the control of cell identity. In particular, we explored the functions of these TUTases in cancer cells, PSCs and muscle progenitors. We found that ZCCHC6/11 contribute to oncogenic transformation and support the growth and tumorigenicity of cancer cell lines. Mechanistically, these effects were associated with altered mRNA uridylation and turnover, including dysregulation of cell cycle factors and concomitant cell cycle impairment. Interestingly, we also report that ZCCHC6/11 promote a less differentiated cell state in both PSCs and lineage-restricted muscle progenitors. Our results reveal novel functions for ZCCHC6/11 and implicate uridylation-mediated mRNA turnover as a mechanism of oncogenesis. Collectively, our work uncovers new post-transcriptional regulatory mechanisms in the control of cell identity, with implications for stem cell and cancer biology.