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Nuclear mRNA processing domain formed by PABPN1 - mRNA phase separation is essential for the growth of oocytes and female reproduction

ABSTRACT: The growing oocytes stored a large amount of maternal mRNA to support the subsequent "maternal-zygotic transition" process, which is a key regulatory events in female reproduction. The accumulation of maternal mRNA in the growing oocyte determines the developmental potential of the oocyte. At present, it is not clear how the growing oocytes store and process the newly transcribed mRNA under physiological conditions, including the distribution and localization of mRNA in the oocyte, as well as the molecular mechanism and physiological significance of this localization. In this study, we found that poly(A) tailed mRNA has the dynamic distributions of droplet fusion and gradual disappearance in the mouse nucleus as oocyte growth and meiotic maturation. Our research found that PABPN1 modulated the dynamic compartmentalization of mRNA with poly(A) tails to form NmPD (nuclear mRNA processing domain) during the growing oocytes through phase separation. The NmPD in Pabpn1-null oocytes could not form the compartmentalized distribution, and the Pabpn1 knockout females were sterile with defects of premature ovarian failure. Combined with multi-omics sequencing analysis, we investigate that NmPD was essential for long 3'-UTR isoform formation and the stability of mRNA in growing oocytes.

ORGANISM(S): Mus musculus

PROVIDER: GSE179406 | GEO | 2021/07/06

REPOSITORIES: GEO

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PABPN1 promotes meiotic maturation of oocytes by interacting with PAPOLA

Project description:Poly(A) polymerase α (PAPα), as the specific mRNA polyadenylation enzyme in the cytoplasm of mammalian oocytes, is essential for oocytes to exclude the first polar body. However, PAPα knockout did not affect germinal vesicles breakdown (GVBD) of oocytes, and the mechanism needs to be further explored. In this study, we identified that PAPα work together with poly(A)-bound RNA binding protein PABPN1 to promote the rupture of germinal vesicles in mammalian oocytes. The protein level of Pabpn1 gradually increases with the meiotic maturation of oocytes. The oocytes specifically knocked out Pabpn1 at the primary follicle stage could develop into the fully grown (FGO) stage, but hardly could enter into the meiotic process. The activated form of CDK1 was injected into Pabpn1-null oocytes, the oocytes could enter into meiotic process. The translational activity of Pabpn1-null oocytes was significantly lower than that of wild-type oocytes during meiosis. In particular, the expression level of protein (BTG4 and CDC25), which were essential for the meiotic maturation of oocytes, were significantly decreased. Therefore, during the oocyte meiosis process, PABPN1 and PAPα jointly promote the oocyte to enter the meiosis process.

2022-08-23 | GSE184028 | GEO

Nuclear Poly(A) Binding Protein 1 (PABPN1) Mediates Zygotic Genome Activation-dependent Maternal mRNA Clearance During Mouse Early Embryonic Development

Project description:An embryo starts its life with maternal mRNA clearance, which is crucial for embryonic development. The elimination of maternal transcripts occurs by the joint action of two pathways: the first is a maternally encoded mRNA decay pathway (M-decay), while the second is zygotic genome activation (ZGA)-dependent pathway (Z-decay). However, the zygotic factors triggering maternal mRNA decay in early mammalian embryos remain largely unknown. In this study, we identify the zygotically encoded nuclear poly(A) binding protein 1 (PABPN1) as a factor required for maternal mRNA turnover, with an unpredictable cytoplasmic function. Cytoplasmic PABPN1 docks on 3ʹ-uridylated transcripts, downstream of terminal uridylyl transferases TUT4 and TUT7, and recruits 3ʹ-5ʹ exoribonuclease DIS3L2 to its targets, facilitating the decay of maternal mRNA. Pabpn1-knockout in mice resulted in preimplantation-stage mortality, due to early developmental arrest at the morula stage. This study characterizes the presence of a zygotic destabilizer of maternal mRNA and helps in elucidating the Z-decay process mechanisms, which potentially contribute to human fertility.

2021-11-25 | GSE174032 | GEO

Pabpn1-driven cytoskeletal rearrangement induces muscle wasting

Project description:Poly(A) binding protein nuclear 1 (PABPN1) is a multifunctional regulator of mRNA processing. PABPN1 inhibits alternative polyadenylation (APA), and in conditions with reduced PABPN1 levels APA utilization causes genome-wide mRNA dysregulation. PABPN1 levels decline from midlife onwards in Oculopharyngeal Muscular Dystrophy (OPMD) and in aged muscles. Reduced PABPN1 levels cause muscle atrophy by altering mRNA levels of the ubiquitin proteasome system. The effect of PABPN1-mediated APA utilization on the proteome has not been investigated yet. We report the PABPN1-mediated proteome in Tibialis anterior (TA) mouse muscles, signifying functional impact for the mitochondria, cytoskeleton and translation cellular machineries. Central nucleation and split myofibers marked PABPN1-derived muscle histology. We show that up-regulation of the cytoskeletal proteins: Murc, Pfn1 and Csrp3, is highly associated with PABPN1-mediated muscle pathology and with reduced PABPN1 levels. Elevation of PABPN1 levels by sirtinol treatment reversed muscle pathology and restored levels of those cytoskeletal proteins. We suggest that restoration of PABPN1 levels in aged muscles could be a novel therapeutic strategy to mitigate muscle waste.

2020-07-06 | PXD004865 | Pride

ZC3H11A interacts with PABPN1 and alters polyadenylation of viral transcripts

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2023-10-24 | PXD042238 | Pride

Nuclear Poly(A)-binding Protein 1-like (PABPN1L) Mediates Cytoplasmic mRNA Decay As a Placeholder during Maternal-to-zygotic Transition

Project description:Maternal mRNA degradation is a critical event of maternal-to-zygotic transition (MZT) that determines the developmental potential of early embryos. Nuclear Poly(A)-binding proteins (PABPNs) are extensively involved in mRNA post-transcriptional regulations, but their functions in mammalian MZT has not been investigated. In this study, we identified a novel maternal-effect factor PABPN1-like (PABPN1L), rather than its ubiquitously expressed homolog PABPN1, as an RNA-binding adapter of the mammalian MZT licensing factor BTG4 which mediates maternal mRNAs clearance. Female Pabpn1l null mice produced morphologically normal oocytes but were infertile owing to early developmental arrest of the resultant embryos at the 1-to-2-cell stages without undergoing ZGA. Deletion of Pabpn1l impairs the deadenylation and degradation of a subset of BTG4-targeted maternal mRNAs during MZT. In addition to recruiting BTG4 to the mRNA 3ʹ-poly(A) tails, PABPN1L is also required for BTG4 protein accumulation in maturing oocytes by protecting BTG4 from SCF-βTrCP1 E3 ubiquitin ligase-mediated polyubiquitination and degradation. This study highlights a noncanonical cytoplasmic function of nuclear poly(A)-binding proteins mRNA turnover as well as its physiological importance during MZT.

2020-05-08 | GSE139072 | GEO

The CCR4-NOT complex suppresses untimely translational activation of maternal mRNAs.

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2023-10-01 | GSE224308 | GEO

Mammalian oocytes store mRNAs in a mitochondria-associated membraneless compartment

Project description:Fully-grown oocytes are transcriptionally silent and must stably maintain mRNAs needed for oocyte meiotic maturation and early embryonic development. However, where and how mammalian oocytes store maternal mRNAs is unclear. Here, we report that mammalian oocytes accumulate mRNAs in a mitochondria-associated ribonucleoprotein domain (MARDO). MARDO assembly around mitochondria was promoted by the RNA-binding protein ZAR1, and directed by an increase in mitochondrial membrane potential during oocyte growth. MARDO foci coalesced into hydrogel-like matrices that clustered mitochondria. Maternal mRNAs stored in the MARDO were translationally repressed. Loss of ZAR1 disrupted the MARDO, dispersed mitochondria, and caused a premature loss of MARDO-localized mRNAs. Thus, a mitochondria-associated membraneless compartment controls mitochondrial distribution and regulates maternal mRNA storage, translation and decay to ensure fertility in mammals.

2022-10-25 | PXD036974 | Pride

LSM14B is essential for oocyte meiotic maturation by regulating maternal mRNA storage and clearance

Project description:Fully grown oocytes remain transcriptionally quiescent, yet many maternal mRNAs are synthesized and retained in growing oocytes. We now know that maternal mRNAs are stored in a structure called the mitochondria associated ribonucleoprotein domain (MARDO). But the components and functions of MARDO remain elusive. Here, we found that LSM14B knockout prevents the proper storage and timely clearance of mRNAs (including Cyclin B1, Btg4, and other mRNAs that are translationally activated during meiotic maturation), specifically by disrupting MARDO assembly during oocyte growth and meiotic maturation. With decreased levels of storage and clearance, the LSM14B knockout oocytes failed to enter meiosis II, ultimately resulting in female infertility. Our results demonstrate the function of LSM14B in MARDO assembly, couple the MARDO with mRNA clearance and oocyte meiotic maturation

2023-10-17 | PXD042761 | Pride

Thorax transcriptome from control and PABPN1-17ala-expressing flies

Project description:Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset syndrome characterized by progressive degeneration of particular muscles. OPMD is caused by short GCG repeat expansions within the gene encoding the nuclear poly(A)-binding protein 1 (PABPN1) that extend an N-terminal polyalanine tract in the protein. Mutant PABPN1 aggregates as nuclear inclusions in OMPD patient muscles. We have created a Drosophila model of OPMD that recapitulates the features of the human disorder: progressive muscle degeneration, with muscle defects proportional to the number of alanines in the tract, and formation of PABPN1 nuclear inclusions. Wild-type human PABPN1 contains a stretch of 10 alanines following the initial methionine, which is expanded to 12–17 alanines in OPMD patients. In Drosophila, the PABPN1 homolog is the poly(A)-binding protein 2 (PABP2), which has the same function as PABPN1 in nuclear polyadenylation but lacks a polyalanine tract at the N-terminus. We used the UAS/Gal4 system to express mammalian PABPN1 in Drosophila. An alanine-expanded PABPN1 cDNA (encoding the 17 alanine tract) was cloned downstream of UAS sequences (UAS-PABPN1). Transgenic lines containing this construct were crossed to a Mhc-Gal4 driver, leading to muscle-specific expression. To gain insight into the molecular and physiological defects in OPMD we performed a transcriptomic analysis in OPMD fly muscles. Using microarrays, thorax gene expression was compared between control flies (Mhc-Gal4/+) and flies expressing PABPN1-17ala in thoracic muscles (UAS-PABPN1-17ala/+; Mhc-Gal4/+), at three time points (days 2, 6 and 11). Transcriptome of thorax RNA samples from control (Mhc-Gal4/+) flies and flies expressing PABPN1-17ala (UAS-PABPN1-17ala/+; Mhc-Gal4/+)

2014-12-12 | GSE64094 | GEO

CPEB1-dependent disruption of the mRNA translation program in oocytes during maternal aging

Project description:The molecular causes of deteriorating oocyte quality during aging are poorly defined. Since oocyte developmental competence relies on post-transcriptional regulations, we tested whether defective mRNA translation contributes to this decline in quality. Disruption in ribosome loading on maternal transcripts is present in old oocytes. Using a candidate approach, we detect altered translation of 3’-UTR-reporters and altered poly(A) length of the endogenous mRNAs. mRNA polyadenylation depends on the cytoplasmic polyadenylation binding protein 1 (CPEB1). Cpeb1 mRNA translation and protein levels are decreased in old oocytes. This decrease causes de-repression of Ccnb1 translation in quiescent oocytes, premature CDK1 activation, and accelerated reentry into meiosis. De-repression of Ccnb1 is corrected by Cpeb1 mRNA injection in old oocytes. Oocyte-specific Cpeb1 haploinsufficiency in young oocytes recapitulates all the translation phenotypes of old oocytes. These findings demonstrate that a dysfunction in the oocyte translation program is associated with the decline in oocyte quality during aging.

2023-01-11 | GSE222638 | GEO

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