The nuclear exosome co-factor MTR4 shapes the transcriptome for meiotic initiation (RNA-Seq)
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1064125 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR30885007_1.fastq.gz | Fastqsanger.gz | |||
| SRR30885007_2.fastq.gz | Fastqsanger.gz |
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Project description:Nuclear RNA decay has emerged as a mechanism for post-transcriptional gene regulation in cultured cells. However, whether this actually occurs in animals and is biologically relevant remains largely unexplored. Here, we demonstrate that MTR4, a central cofactor of the nuclear RNA exosome complex, is required for embryogenesis and spermatogenesis. Embryonic development of MTR4 knockout mice arrests at 6.5 days. Specific knock out of MTR4 in mouse advanced germ cells results in male infertility with a severe defect in meiotic initiation, with pre-meiotic germ cells accumulating a dysregulated transcriptome with mixed features of mitosis and meiosis. Interestingly, MTR4 pervasively binds to various types of RNAs but selectively degrades those exhibiting specific binding patterns. Moreover, polyadenylated retrotransposon RNAs are removed by the nuclear exosome, preventing their negative impacts on gene expression and potential mutagenic threat. Our work underscores the importance of nuclear RNA decay in regulating germline transcripts to ensure a gene expression program for the mitotic-to-meiotic transition.
2025-02-23 | GSE253156 | GEO
Project description:Nuclear RNA decay has emerged as a mechanism for post-transcriptional gene regulation in cultured cells. However, whether this actually occurs in animals and is biologically relevant remains largely unexplored. Here, we demonstrate that MTR4, a central cofactor of the nuclear RNA exosome complex, is required for embryogenesis and spermatogenesis. Embryonic development of MTR4 knockout mice arrests at 6.5 days. Specific knock out of MTR4 in mouse advanced germ cells results in male infertility with a severe defect in meiotic initiation, with pre-meiotic germ cells accumulating a dysregulated transcriptome with mixed features of mitosis and meiosis. Interestingly, MTR4 pervasively binds to various types of RNAs but selectively degrades those exhibiting specific binding patterns. Moreover, polyadenylated retrotransposon RNAs are removed by the nuclear exosome, preventing their negative impacts on gene expression and potential mutagenic threat. Our work underscores the importance of nuclear RNA decay in regulating germline transcripts to ensure a gene expression program for the mitotic-to-meiotic transition.
2025-02-23 | GSE253154 | GEO
Project description:The nuclear exosome co-factor MTR4 shapes the transcriptome for meiotic initiation (LACE-Seq)
| PRJNA1064128 | ENA
Project description:The exosome functions in the degradation of diverse RNA species, yet how it is negatively regulated remains largely unknown. Here, we show that NRDE2 forms a 1:1 complex with MTR4, a nuclear exosome cofactor critical for exosome recruitment, via a conserved MTR4-interacting domain (MID). Unexpectedly, NRDE2 mainly localizes in nuclear speckles, where it inhibits MTR4 recruitment and RNA degradation, and thereby ensures efficient mRNA nuclear export. Structural and biochemical data revealed that NRDE2 interacts with MTR4's key residues, locks MTR4 in a closed conformation, and inhibits MTR4 interaction with the exosome as well as proteins important for MTR4 recruitment, such as the cap-binding complex (CBC) and ZFC3H1. Functionally, MID deletion results in the loss of self-renewal of mouse embryonic stem cells. Together, our data pinpoint NRDE2 as a nuclear exosome negative regulator that ensures mRNA stability and nuclear export.
2019-03-14 | GSE120206 | GEO
Project description:til-ath-2011_3 - tiling hen2 and mtr4 - Identification and comparison of the RNA substrates that accumulate in hen2 and mtr4 mutants. Total RNA extracted from WT, hen2 and mtr4 mutants was used for oligo-dT primed cDNA preparation. Samples were hybridised to NimbleGen whole genome tiling arrays. 8 dye-swapped samples. Gene knockout, genotype comparison, normal vs. transgenic comparison.
2013-06-30 | E-GEOD-48178 | biostudies-arrayexpress
Project description:Ray2013 - Meiotic initiation in S. cerevisiae
A mathematical representation of early meiotic events, particularly feedback mechanisms at the system level and phosphorylation of signalling molecules for regulating protein activities, is described here
This model is described in the article:
Dynamic modeling of yeast meiotic initiation.
Ray D, Su Y, Ye P.
BMC Syst Biol. 2013 May 1;7:37
Abstract:
BACKGROUND:
Meiosis is the sexual reproduction process common to eukaryotes. The diploid yeast Saccharomyces cerevisiae undergoes meiosis in sporulation medium to form four haploid spores. Initiation of the process is tightly controlled by intricate networks of positive and negative feedback loops. Intriguingly, expression of early meiotic proteins occurs within a narrow time window. Further, sporulation efficiency is strikingly different for yeast strains with distinct mutations or genetic backgrounds. To investigate signal transduction pathways that regulate transient protein expression and sporulation efficiency, we develop a mathematical model using ordinary differential equations. The model describes early meiotic events, particularly feedback mechanisms at the system level and phosphorylation of signaling molecules for regulating protein activities.
RESULTS:
The mathematical model is capable of simulating the orderly and transient dynamics of meiotic proteins including Ime1, the master regulator of meiotic initiation, and Ime2, a kinase encoded by an early gene. The model is validated by quantitative sporulation phenotypes of single-gene knockouts. Thus, we can use the model to make novel predictions on the cooperation between proteins in the signaling pathway. Virtual perturbations on feedback loops suggest that both positive and negative feedback loops are required to terminate expression of early meiotic proteins. Bifurcation analyses on feedback loops indicate that multiple feedback loops are coordinated to modulate sporulation efficiency. In particular, positive auto-regulation of Ime2 produces a bistable system with a normal meiotic state and a more efficient meiotic state.
CONCLUSIONS:
By systematically scanning through feedback loops in the mathematical model, we demonstrate that, in yeast, the decisions to terminate protein expression and to sporulate at different efficiencies stem from feedback signals toward the master regulator Ime1 and the early meiotic protein Ime2. We argue that the architecture of meiotic initiation pathway generates a robust mechanism that assures a rapid and complete transition into meiosis. This type of systems-level regulation is a commonly used mechanism controlling developmental programs in yeast and other organisms. Our mathematical model uncovers key regulations that can be manipulated to enhance sporulation efficiency, an important first step in the development of new strategies for producing gametes with high quality and quantity.
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2024-09-02 | BIOMD0000000626 | BioModels
Project description:Recent in vitro reconstitution analyses have proven that the physical interaction between the exosome core and MTR4 helicase, which promotes the exosome activity, is maintained by either MPP6 or RRP6. However, knowledge regarding the function of MPP6 with respect to in vivo exosome activity remains scarce. Here we demonstrate a facilitative function of MPP6 that composes a specific part of MTR4-dependent substrate decay by the human exosome. Using RNA polymerase II-transcribed poly(A)+ substrate accumulation as an indicator of a perturbed exosome, we found functional redundancy between RRP6 and MPP6 in the decay of these poly(A)+ transcripts. MTR4 binding to the exosome core via MPP6 was essential for MPP6 to exert its redundancy with RRP6. However, at least for the decay of our identified exosome substrates, MTR4 recruitment by MPP6 was not functionally equivalent to recruitment by RRP6. Genome-wide classification of substrates based on their sensitivity to each exosome component revealed that MPP6 deals with a specific range of substrates, and highlights the importance of MTR4 for their decay. Considering recent findings of competitive binding to the exosome between auxiliary complexes, our results suggest that the MPP6-incorporated MTR4-exosome complex is one of multiple alternative complexes rather than the prevailing one.
2022-06-19 | GSE184274 | GEO
Project description:In mammalian testes, premeiotic spermatogonia respond to retinoic
acid by completing an essential lengthy differentiation program before
initiating meiosis. The molecular and cellular changes directing these
developmental processes remain largely undefined. This wide gap in
knowledge is due to two critical unresolved technical challenges: (1)
lack of robust and reliable in vitro models to study differentiation and
meiotic initiation; and (2) lack of methods to isolate large and pure
populations of male germ cells at each stage of differentiation and at
meiotic initiation. Here, we report a facile in vitro differentiation and
meiotic initiation system that can be readily manipulated, including the
use of chemical agents that cannot be safely administered to live
animals. In addition, we present a transgenic mouse model enabling
fluorescence-activated cell sorting-based isolation of millions of
spermatogonia at specific developmental stages as well as meiotic
spermatocytes
2022-10-28 | PXD037781 | JPOST Repository
Project description:Metabolic switch from oxidative phosphorylation to glycolysis is required for tumorigenesis by providing cancer cells with energy and substrates of biosynthesis, and also plays a key role in inducing immune suppressive tumor microenvironment that inhibits tumor immunotherapy. Therefore, to develop more effective cancer therapy, it is important to elucidate mechanisms that control cancer metabolic switch. MTR4 is a RNA helicase associated with nuclear exosome that plays key roles in RNA processing and surveillance. We demonstrated that MTR4 is frequently overexpressed in hepatocellular carcinoma (HCC) and this predicts poor prognosis of HCC patients. MTR4 is required for HCC tumorigenesis by maintaining cancer metabolic switch. Mechanistically, MTR4 is required for the expression of critical glycolytic proteins such as GLUT1 and PKM2 by binding to their pre-mRNA and ensuring correct alternative splicing. c-Myc binds to the promoter of MTR4 gene and is required for MTR4 expression, indicating that MTR4 is a key mediator of c-Myc function in promoting cancer metabolism. These findings reveal an important pathway to drive cancer metabolic switch and present MTR4 as a promising therapeutic target for treating HCC.
2019-12-19 | GSE129261 | GEO
Project description:Mtr4 is a eukaryotic RNA helicase required for RNA decay by the nuclear exosome. Previous studies have shown how RNA enroute to the exosome threads through the highly conserved helicase core of Mtr4. Mtr4 also contains an arch domain, although details of potential interactions between the arch and RNA have been elusive. To understand the interaction of Saccharomyces cerevisiae Mtr4 with various RNAs, we have characterized RNA binding in solution using hydrogen-deuterium exchange mass spectrometry, and affinity and unwinding assays. We have identified RNA interactions within the helicase core that are consistent with existing structures and do not vary between tRNA, single-stranded RNA, and double-stranded RNA constructs. We have also identified novel RNA interactions with a region of the arch known as the fist or KOW. These interactions are important for RNA unwinding and vary in strength depending on RNA structure and length. They account for Mtr4 discrimination between different RNAs. These interactions further drive Mtr4 to adopt a closed conformation characterized by reduced dynamics of the arch arm and intra-domain contacts between the fist and helicase core.
2022-03-07 | PXD031962 | Pride