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RNA degradation eliminates developmental transcripts during murine embryonic stem cell differentiation via CAPRIN1-XRN2.

ABSTRACT: Embryonic stem cells (ESCs) are self-renewing and pluripotent. In recent years, factors that control pluripotency, mostly nuclear, have been identified. To identify non-nuclear regulators of ESCs, we screened an endogenously labeled fluorescent fusion-protein library in mouse ESCs. One of the more compelling hits was the cell-cycle-associated protein 1 (CAPRIN1). CAPRIN1 knockout had little effect in ESCs, but it significantly altered differentiation and gene expression programs. Using RIP-seq and SLAM-seq, we found that CAPRIN1 associates with, and promotes the degradation of, thousands of RNA transcripts. CAPRIN1 interactome identified XRN2 as the likely ribonuclease. Upon early ESC differentiation, XRN2 is located in the nucleus and colocalizes with CAPRIN1 in small RNA granules in a CAPRIN1-dependent manner. We propose that CAPRIN1 regulates an RNA degradation pathway operating during early ESC differentiation, thus eliminating undesired spuriously transcribed transcripts in ESCs.

SUBMITTER: Viegas JO

PROVIDER: S-EPMC9796812 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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RNA degradation eliminates developmental transcripts during murine embryonic stem cell differentiation via CAPRIN1-XRN2.

Viegas Juliane O JO Azad Gajendra Kumar GK Lv Yuan Y Fishman Lior L Paltiel Tal T Pattabiraman Sundararaghavan S Park Jung Eun JE Kaganovich Daniel D Sze Siu Kwan SK Rabani Michal M Esteban Miguel A MA Meshorer Eran E

Developmental cell 20221209 24

Embryonic stem cells (ESCs) are self-renewing and pluripotent. In recent years, factors that control pluripotency, mostly nuclear, have been identified. To identify non-nuclear regulators of ESCs, we screened an endogenously labeled fluorescent fusion-protein library in mouse ESCs. One of the more compelling hits was the cell-cycle-associated protein 1 (CAPRIN1). CAPRIN1 knockout had little effect in ESCs, but it significantly altered differentiation and gene expression programs. Using RIP-seq a ...[more]

PMID: 36495875

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Project description:Glycosaminoglycans (GAGs) play a critical role in binding and activation of growth factors involved in cell signaling critical for developmental biology. The biosynthetic pathways for GAGs have been elucidated over the past decade and now analytical methodology makes it possible to determine GAG composition in as few as 10 million cells. A glycomics approach was used to examine GAG content, composition, and the level of transcripts encoding for GAG biosynthetic enzymes as murine embryonic stem cells (mESCs) differentiate to embryoid bodies (EBs) and to extraembryonic endodermal cells (ExE) to better understand the role of GAGs in stem cell differentiation. Hyaluronan synthesis was enhanced by 13- and 24-fold, most likely due to increased expression of hyaluronan synthase-2. Chondroitin sulfate (CS)/dermatan sulfate (DS) synthesis was enhanced by 4- and 6-fold, and heparan sulfate (HS) synthesis was enhanced by 5- and 8-fold following the transition from mESC to EB and ExE. Transcripts associated with the synthesis of the early precursors were largely unaltered, suggesting other factors account for enhanced GAG synthesis. The composition of both CS/DS and HS also changed upon differentiation. Interestingly, CS type E and highly sulfated HS both increase as mESCs differentiate to EBs and ExE. Differentiation was also accompanied by enhanced 2-sulfation in both CS/DS and HS families. Transcript levels for core proteins generally showed increases or remained constant upon mESC differentiation. Finally, transcripts encoding selected enzymes and isoforms, including GlcNAc-4,6-O-sulfotransferase, C5-epimerases, and 3-O-sulfotransferases involved in late GAG biosynthesis, were also enriched. These biosynthetic enzymes are particularly important in introducing GAG fine structure, essential for intercellular communication, cell adhesion, and outside-in signaling. Knowing the changes in GAG fine structure should improve our understanding the biological properties of differentiated stem cells.

Dataset Information

RNA degradation eliminates developmental transcripts during murine embryonic stem cell differentiation via CAPRIN1-XRN2.

Publications

RNA degradation eliminates developmental transcripts during murine embryonic stem cell differentiation via CAPRIN1-XRN2.

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