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Peg10 eCLIP in pluripotent trophoblast stem cells

ABSTRACT: The prevailing dogma that approximately 50% of our genome is “junk” DNA composed of transposable elements and retroviral insertions has recently been challenged. It has become evident that our genome has taken advantage of these transposable elements and uses them as a source of DNA to generate novel genes, which subsequently allow the organism to evolve. This process is termed “domestication of transposable elements” and the majority of these genes have been found to be essential for the existence of the organism. One of these developmentally essential domesticated genes: Peg10 (paternally expressed gene 10), was derived from a Ty3/gyspy LTR retrotransposon, yet lost its ability to transpose due to mutational events during its domestication. Remarkably, Peg10 has successfully maintained its Gag and Pol-like domains for millions of years. Peg10 orthologues are expressed in eutherian mammals and are essential for placentogenesis. To address the functional mechanisms of Peg10 we studied it in Trophoblast Stem Cells (TSCs). We find that the Gag of Peg10 is fully active: it promotes budding of vesicles, akin to the viral counterpart that catalyzes the budding of viruses. TSCs, deleted for Peg10, fail to differentiate into placental lineages, underscoring a critical role in lineage specification. This paper discusses our efforts to characterize the contents of Peg10 vesicles and whether such vesicles regulate lineage specification.

ORGANISM(S): Mus musculus

PROVIDER: GSE122216 | GEO | 2019/03/22

REPOSITORIES: GEO

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Peg10 regulation of TSC differentiation

Project description:The prevailing dogma that approximately 50% of our genome is “junk” DNA composed of transposable elements and retroviral insertions has recently been challenged. It has become evident that our genome has taken advantage of these transposable elements and uses them as a source of DNA to generate novel genes, which subsequently allow the organism to evolve. This process is termed “domestication of transposable elements” and the majority of these genes have been found to be essential for the existence of the organism. One of these developmentally essential domesticated genes: Peg10 (paternally expressed gene 10), was derived from a Ty3/gyspy LTR retrotransposon, yet lost its ability to transpose due to mutational events during its domestication. Remarkably, Peg10 has successfully maintained its Gag and Pol-like domains for millions of years. Peg10 orthologues are expressed in eutherian mammals and are essential for placentogenesis. To address the functional mechanisms of Peg10 we studied it in Trophoblast Stem Cells (TSCs). We find that the Gag of Peg10 is fully active: it promotes budding of vesicles, akin to the viral counterpart that catalyzes the budding of viruses. TSCs, deleted for Peg10, fail to differentiate into placental lineages, underscoring a critical role in lineage specification. This paper discusses our efforts to characterize the contents of Peg10 vesicles and whether such vesicles regulate lineage specification.

2019-03-22 | GSE122215 | GEO

The Gag Protein PEG10 Binds to RNA and Regulates Trophoblast Stem Cell Lineage Specification

Project description:Peg10 (paternally expressed gene 10) is an imprinted gene that is essential for placental development (1). It is thought to derive from a Ty3-gyspy LTR (long terminal repeat) retrotransposon and retains Gag and Pol-like domains (2). Here we show that the Gag domain of PEG10 can promote vesicle budding similar to the HIV p24 Gag protein. Expressed in a subset of mouse endocrine organs in addition to the placenta, PEG10 was identified as a substrate of the deubiquitinating enzyme USP9X. Consistent with PEG10 having a critical role in placental development, PEG10-deficient trophoblast stem cells (TSCs) exhibited impaired differentiation into placental lineages. PEG10 expressed in wild-type, differentiating TSCs was bound to many cellular RNAs including Hbegf (Heparin-binding EGF-like growth factor), which is known to play an important role in placentation (3). Expression of Hbegf was reduced in PEG10-deficient TSCs suggesting that PEG10 might bind to and stabilize RNAs that are critical for normal placental development.

2018-12-14 | MSV000083229 | MassIVE

Gene expression changes in HEK293 cells following PEG10 overexpression.

Project description:The goal of this study was to determine transcriptional changes in HEK293 cells upon overexpression of various forms of Paternally Expressed Gene 10, or PEG10. Cells were transfected either with control, or with PEG10 gag, gag-pol, or isolated NC fragment constructs and RNA isolated for RNA-Seq analysis.

2023-03-29 | GSE227789 | GEO

UBQLN2 restrains the domesticated retrotransposon PEG10 to maintain neuronal health in ALS

Project description:Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative disease characterized by motor neuron dysfunction and loss, leading to progressive paralysis and death. A portion of ALS cases is caused by mutation of the proteasome shuttle factor Ubiquilin 2 (UBQLN2), but the molecular pathway leading from UBQLN2 dysfunction to neurodegenerative disease remains unclear. Here, we demonstrate a major function of UBQLN2 in regulating activity of the domesticated gag-pol retrotransposon ‘paternally expressed gene 10’ (PEG10) in human cells and tissues. UBQLN2 exclusively facilitates degradation of the frameshifted gag-pol form of PEG10 through recognition of a unique polyproline repeat. In cells, the PEG10 gag-pol protein cleaves itself in a mechanism reminiscent of retrotransposon self-processing to generate a liberated ‘nucleocapsid’ fragment, which uniquely localizes to the nucleus. Overexpression of the nucleocapsid fragment upregulates transcription of neuronal genes involved in axon remodeling, which were also affected in sporadic ALS (sALS) patient tissues. Finally, proteomics of spinal cords from ALS patients revealed that PEG10 gag-pol is significantly elevated in disease compared to healthy controls. These findings implicate the retrotransposon-like activity of PEG10 as a contributing mechanism in ALS through regulation of neuronal gene expression, and restraint of PEG10 as a primary function of UBQLN2.

2023-03-24 | PXD031964 | Pride

Gag proteins encoded by endogenous retroviruses are required for zebrafish development

Project description:Transposable elements (TEs) make up the bulk of eukaryotic genomes and examples abound of TE-derived sequences repurposed for organismal function. The process by which TEs become coopted remains obscure because most cases involve ancient, transpositionally inactive elements. Reports of active TEs serving beneficial functions are scarce and often contentious due to difficulties in manipulating repetitive sequences. Here we show that recently active TEs in zebrafish encode products critical for embryonic development. Knockdown and rescue experiments demonstrate that the endogenous retrovirus family BHIKHARI-1 (Bik-1) encodes a Gag protein essential for mesoderm development. Mechanistically, Bik-1 Gag associates with the cell membrane and its ectopic expression in chicken embryos alters cell migration. Similarly, depletion of BHIKHARI-2 Gag, a relative of Bik-1, causes defects in neural crest development in zebrafish. We propose an “addiction” model to explain how active TEs can be integrated into conserved developmental processes.

2024-04-04 | GSE263091 | GEO

A Domestication-Selected Retrotransposon for Quenching Genomic Immunity in Rice [MeDIP-seq]

Project description:Transposable elements (TEs) are genomic parasites that constitute the most abundant portions of higher plant genomes. However, whether TE selection occurred during crop domestication remains unknown. HUO is active under normal growth conditions, present at low copy numbers, inserts preferentially into regions capable of transcription, but absent in almost all modern varieties, indicating its removal during rice domestication and modern rice breeding. HUO triggers genomic immunity and dramatically alters genome-wide methylation levels and small RNA biogenesis, as well as global gene expression. Its presence specifically affects agronomic traits by decreasing yield performance and disease resistance but enhancing salt tolerance, which mechanistically explains its domestication removal. Thus, our study reveals a unique retrotransposon as a negative target for maintaining genetic and epigenetic stability during crop domestication and selection.

2018-03-08 | GSE79155 | GEO

A Domestication-Selected Retrotransposon for Quenching Genomic Immunity in Rice [small RNA-Seq]

2018-03-08 | GSE78900 | GEO

A Domestication-Selected Retrotransposon for Quenching Genomic Immunity in Rice [RNA-Seq]

2018-03-08 | GSE78883 | GEO

A Domestication-Selected Retrotransposon for Quenching Genomic Immunity in Rice [Bisulfite-seq]

2018-03-08 | GSE79154 | GEO

Secreted retrovirus-like GAG domain containing protein PEG10 is regulated by UBE3A and is involved in Angelman syndrome pathophysiology

Project description:Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by mutations that effect expression of the maternal UBE3A allele, which encodes the ubiquitin protein ligase E3A (UBE3A). Although several potential UBE3A targets have been identified, our understanding of relevant disease targets is very limited, and validation in patient-derived cells is lacking. We established human iPSC (hiPSC) control and AS patient-derived neuronal models and demonstrate specific and reciprocal modulation of UBE3A using anti-sense oligonucleotides (ASOs). Through unbiased proteomic analysis we identified proteins whose abundance were directly affected by manipulating UBE3A levels, including the novel human specific PEG10 protein, a secreted retrotransposon derived GAG domain-containing protein. PEG10 protein, but not RNA, was elevated in AS hiPSC-derived neurons as well as in postmortem AS brain tissue, and we showed that its upregulation in patient-derived cells is dependent on both UBE3A and normal proteasome function. Functional analysis revealed that PEG10 binds both RNA and ataxia associated proteins, ATXN2 and ATXN10. PEG10 localizes to stress granules and is secreted in extracellular vesicles, where it regulates vesicle content. AS patient-derived neurons in which either UBE3A was reinstated or PEG10 was reduced, showed a striking similarity in transcriptome changes. In addition, overexpression of PEG10 during mouse brain development affected the migration of the PEG10-overexpressing neurons, suggesting that PEG10 overexpression can affect neuronal function at a critical time during brain development. Taken together these findings imply that PEG10 is a novel secreted UBE3A target, and is involved in AS pathophysiology.

2021-06-18 | MSV000087654 | MassIVE

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