Dual repression of endocytic players by ESCC microRNAs and the Polycomb complex regulates mouse embryonic stem cell pluripotency

Abstract

Cell fate determination in the early mammalian embryo is regulated by multiple mechanisms. Recently, genes involved in vesicular trafficking have been shown to play an important role in cell fate choice, although the regulation of their expression remains poorly understood. Here we demonstrate for the first time that multiple endocytosis associated genes (EAGs) are repressed through a novel, dual mechanism in mouse embryonic stem cells (mESCs). This involves the action of the Polycomb Repressive Complex, PRC2, as well as post-transcriptional regulation by the ESC-specific cell cycle-regulating (ESCC) family of microRNAs. This repression is relieved upon differentiation. Forced expression of EAGs in mESCs results in a decrease in pluripotency, highlighting the importance of dual repression in cell fate regulation. We propose that endocytosis is critical for cell fate choice, and dual repression may function to tightly regulate levels of endocytic genes.

Clathrin-Mediated Endocytosis Regulates a Balance between Opposing Signals to Maintain the Pluripotent State of Embryonic Stem Cells

“…Embryonic stem cells (ESCs) isolated from the inner cell mass of the blastocyst represent a wonderful model system to follow developmental decisions and cell fate transitions in vitro (Evans, 2011, Evans and Kaufman, 1981, Martin, 1981). Recent reports have demonstrated that endocytosis plays a role in regulating the acquisition, as well as the maintenance of the pluripotent state (Dambournet et al., 2018, Li et al., 2010, Mote et al., 2017, Qin et al., 2014, Subramanyam et al., 2011). Endocytosis is a fundamental eukaryotic process, wherein membrane-bound proteins are trafficked to different compartments of the cell depending on their function, with the help of small GTPases called RABs (Doherty and McMahon, 2009, Traub, 2009).…”

Cell Profiling Based on Sugar‐Chain–Cell Binding Interaction and Its Application to Typing and Quality Verification of Cells

“…Conversely, the binding of anionic SAα2‐6Gal‐ and SAα2‐3Gal‐SFNPs was increased in PrECs. Genes related to multiple endocytosis are repressed in mouse ESCs, and the suppression is weakened during differentiation; this might enhance uptake of anionic SFNPs through the endocytic process. Furthermore, CD44, which is a hyaluronate receptor and increases during differentiation, might be involved in increasing the binding potency of anionic SFNPs .…”

MicroRNAs reinforce repression of PRC2 transcriptional targets independently and through a feed-forward regulatory network

“…PRC2 and miRNAs were recently shown to independently corepress endocytosis genes in mESCs (Mote et al 2017). To test if miRNAs and PRC2 repressed a common set of genes independently in GBM cells, we depleted miRNAs globally by overexpressing VP55 in EZH2 −/− T98G cells and performed miRNA-seq and mRNA-seq.…”