Fip1 regulates mRNA alternative polyadenylation to promote stem cell self-renewal

Synopsis image Alternative polyadenylation is an emerging key post-transcriptional regulatory mechanism. The essential role for mRNA 3 ' end processing factor Fip1 in stem cell self-renewal and pluripotency reveals the importance of poly(A) site choice. mRNA alternative polyadenylation is critical for stem cell self-renewal and pluripotency Fip1 is a key regulator of mRNA alternative polyadenylation The direction of alternative polyadenylation switch is controlled by Fip1 binding and the distance between alternative poly(A) sites Abstract mRNA alternative polyadenylation (APA) plays a critical role in post-transcriptional gene control and is highly regulated during development and disease. However, the regulatory mechanisms and functional consequences of APA remain poorly understood. Here, we show that an mRNA 3 ' processing factor, Fip1, is essential for embryonic stem cell (ESC) self-renewal and somatic cell reprogramming. Fip1 promotes stem cell maintenance, in part, by activating the ESC-specific APA profiles to ensure the optimal expression of a specific set of genes, including critical self-renewal factors. Fip1 expression and the Fip1-dependent APA program change during ESC differentiation and are restored to an ESC-like state during somatic reprogramming. Mechanistically, we provide evidence that the specificity of Fip1-mediated APA regulation depends on multiple factors, including Fip1-RNA interactions and the distance between APA sites. Together, our data highlight the role for post-transcriptional control in stem cell self-renewal, provide mechanistic insight on APA regulation in development, and establish an important function for APA in cell fate specification.