Abstract
Pseudogene-derived, long non-coding RNAs (lncRNAs) act as epigenetic regulators of gene expression. Here we present a panel of new mouse Oct4 pseudogenes and demonstrate that the X-linked Oct4 pseudogene Oct4P4 critically impacts mouse embryonic stem cells (mESCs) self-renewal. Sense Oct4P4 transcription produces a spliced, nuclear-restricted lncRNA that is efficiently upregulated during mESC differentiation. Oct4P4 lncRNA forms a complex with the SUV39H1 HMTase to direct the imposition of H3K9me3 and HP1α to the promoter of the ancestral Oct4 gene, located on chromosome 17, leading to gene silencing and reduced mESC self-renewal. Targeting Oct4P4 expression in primary mouse embryonic fibroblasts causes the re-acquisition of self-renewing features of mESC. We demonstrate that Oct4P4 lncRNA plays an important role in inducing and maintaining silencing of the ancestral Oct4 gene in differentiating mESCs. Our data introduces a sense pseudogene–lncRNA-based mechanism of epigenetic gene regulation that controls the cross-talk between pseudogenes and their ancestral genes.
Highlights
Pseudogene-derived, long non-coding RNAs act as epigenetic regulators of gene expression
Pseudogene-derived transcripts have been reported to impact on the expression of ancestral protein-coding gene using molecular pathways based on RNA sequence homology
Dramatic upregulation of sense Oct4P4 transcription during mouse embryonic stem cells (mESCs) differentiation gives rise to a long, non-coding RNA that forms a complex with the repressive H3K9-specific HMTase SUV39H1
Summary
Pseudogene-derived, long non-coding RNAs (lncRNAs) act as epigenetic regulators of gene expression. We found that a long, non-coding RNA transcribed in sense orientation from Oct[4] pseudogene 4 (Oct4P4) recruits the H3K9-specific HMTase SUV39H1 to induce epigenetic repression of the promoter of the ancestral Oct[4] gene in trans This mechanism reduces the expression of key self-renewal transcription factors and promotes mESC differentiation. Oct4P1, gapdh and the ancestral Oct[4] mRNA show enrichment in the cytoplasm; Oct4P3 and Oct4P5 did not show specific enrichment in nucleus or cytoplasm of mESCs (Fig. 1d) Together, these data indicate that a subset of RNAs derived from Oct[4] pseudogenes show controlled intracellular localization and tight transcriptional regulation, anticipating a potential role in the control of mESC self-renewal. Unique properties of the Oct4P4 lncRNA such as extended homology to the ancestral Oct[4] gene, nuclear localization, splicing, efficient upregulation during mESC differentiation and the virtual absence of relevant ORFs (Supplementary Fig. 1d) prompted us to investigate a possible role of Oct4P4 in the control of mESC differentiation and self-renewal
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
