The RNA exosome nuclease complex regulates human embryonic stem cell differentiation

Abstract

A defining feature of embryonic stem cells (ESCs) is the ability to differentiate into all three germ layers. Pluripotency is maintained in part by a unique transcription network that maintains expression of pluripotency-specific transcription factors and represses developmental genes. While the mechanisms that establish this transcription network are well studied, little is known of the posttranscriptional surveillance pathways that degrade differentiation-related RNAs. We report that the surveillance pathway mediated by the RNA exosome nuclease complex represses ESC differentiation. Depletion of the exosome expedites differentiation of human ESCs into all three germ layers. LINE-1 retrotransposons and specific miRNAs, lncRNAs, and mRNAs that encode developmental regulators or affect their expression are all bound by the exosome and increase in level upon exosome depletion. The exosome restrains differentiation in part by degrading transcripts encoding FOXH1, a transcription factor crucial for mesendoderm formation. Our studies establish the exosome as a regulator of human ESC differentiation and reveal the importance of RNA decay in maintaining pluripotency.

A precision RNA degradation machinery shapes stem cell development

“…In summary, the study by Belair et al (12) supports the idea that RNA decay pathways make key contributions to regulate the fate of hESCs. The work also sheds light on an important connection between exosome, differentiation, and pluripotency.…”

“…The FOXH1 (Forkhead box protein H1) mRNA was identified by Belair et al (12) as an important player that could account for the repression of hESC differentiation by exosomes. FOXH1 is a crucial TF for genes such as NODAL, LEFTY1, CER1, and MIXL1, which are involved in the formation of the mesendoderm (ME), the precursor to mesoderm and endoderm.…”

“…The current study provides evidence that exosome restrains hESC differentiation by a mechanism that includes reduction of the expression of FOXH1 mRNA. Belair et al suggest an additional role for the exosome in maintaining hESC pluripotency by selective degradation of RNAs that encode key developmental regulators (12). A pri-miRNA was identified as a target of the exosome (i.e., the EXOSC10-containing exosomes affect miR-205 levels by reducing the pri-miRNA).…”

ADrosophilaModel of Pontocerebellar Hypoplasia Reveals a Critical Role for the RNA Exosome in Neurons

“…Thus, identification of mutations in genes encoding structural Morton et al 12 subunits of the RNA exosome that cause tissue-specific pathology was unexpected. In fact, only a few studies have explored the requirement for the RNA exosome in any specific tissues or cell types [11,[23][24][25]. Prior work using methods to deplete individual subunits of the complex in Drosophila, revealed that these subunits are essential [11,26].…”

“…Prior work using methods to deplete individual subunits of the complex in Drosophila, revealed that these subunits are essential [11,26]. More recent work examining the role of the EXOSC3 subunit in human embryonic stem cells built on studies that have implicated the RNA exosome in restraining differentiation [23][24][25]. If there are specific requirements for the RNA exosome that are most critical for the development and/or homeostasis of certain cells or tissues, this could explain why mutations that impair the function of this complex could preferentially affect certain tissues.…”