RNA Decay in Processing Bodies is Indispensable for Adipogenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA700985 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13668105_1.fastq.gz | Fastqsanger.gz | |||
| SRR13668105_2.fastq.gz | Fastqsanger.gz | |||
| SRR13668106_1.fastq.gz | Fastqsanger.gz | |||
| SRR13668106_2.fastq.gz | Fastqsanger.gz | |||
| SRR13668107_1.fastq.gz | Fastqsanger.gz |
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Project description:The RNA decay pathway plays key regulatory roles in cell identities and differentiation processes. Although adipogenesis is transcriptionally and epigenetically regulated and has been thoroughly investigated, how RNA metabolism that contributes to the stability of phenotype-shaping transcriptomes participates in differentiation remains elusive. In this study, we investigated Ddx6, an essential component of processing bodies (PBs) that executes RNA decay and translational repression in the cytoplasm and participates in the cellular transition of reprogramming. Upon adipogenic induction, Ddx6 dynamically accumulated to form PBs with a binding partner, 4E-T, at the early phase prior to emergence of intracellular lipid droplets. In contrast, preadipocytes with Ddx6 knockout (KO) or 4E-T knockdown (KD) failed to generate PBs, resulting in significant suppression of adipogenesis. Transcription factors related to preadipocytes and negative regulators of adipogenesis that were not expressed under adipogenic stimulation were maintained in Ddx6-KO and 4E-T-KD preadipocytes under adipogenic induction. Elimination of Dlk1, a major negative regulator of adipogenesis, in 3T3L1 Ddx6-KO cells did not restore adipogenic differentiation capacity to any extent. Similar to murine cells, human primary mesenchymal stem cells, which can differentiate into adipocytes upon stimulation with adipogenic cocktails, required DDX6 to maturate into adipocytes. Therefore, RNA decay of the entire parental transcriptome, rather than removal of a strong negative regulator, could be indispensable for adipogenesis.
2021-02-10 | GSE166450 | GEO
Project description:The RNA decay pathway plays key regulatory roles in cell identities and differentiation processes. Although adipogenesis is transcriptionally and epigenetically regulated and has been thoroughly investigated, how RNA metabolism that contributes to the stability of phenotype-shaping transcriptomes participates in differentiation remains elusive. In this study, we investigated Ddx6, an essential component of processing bodies (PBs) that executes RNA decay and translational repression in the cytoplasm and participates in the cellular transition of reprogramming. Upon adipogenic induction, Ddx6 dynamically accumulated to form PBs with a binding partner, 4E-T, at the early phase prior to emergence of intracellular lipid droplets. In contrast, preadipocytes with Ddx6 knockout (KO) or 4E-T knockdown (KD) failed to generate PBs, resulting in significant suppression of adipogenesis. Transcription factors related to preadipocytes and negative regulators of adipogenesis that were not expressed under adipogenic stimulation were maintained in Ddx6-KO and 4E-T-KD preadipocytes under adipogenic induction. Elimination of Dlk1, a major negative regulator of adipogenesis, in 3T3L1 Ddx6-KO cells did not restore adipogenic differentiation capacity to any extent. Similar to murine cells, human primary mesenchymal stem cells, which can differentiate into adipocytes upon stimulation with adipogenic cocktails, required DDX6 to maturate into adipocytes. Therefore, RNA decay of the entire parental transcriptome, rather than removal of a strong negative regulator, could be indispensable for adipogenesis.
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Project description:The synthesis and decay of mRNA in cells are carried out by influencing each other, and their balance is altered by either external or internal cues, resulting in changes in the dynamics of the cell. We have previously reported that it is indispensable that an array of mRNAs which shape a phenotype should be degraded before cellular transitions, such as cellular reprogramming and differentiation. In adipogenesis, the interaction between DDX6 and 4E-T had a definitive impact on the pathway in the processing body (PB). We screened a library of α-helix analog with an alkaloid backbone to determine a compound inhibiting the binding between DDX6 and 4E-T proteins, because the interaction is executed between α-helix of structured and internally disordered protein, respectively, and identified IAMC-00192 as a lead compound. The compound showed a direct inhibition in the interaction between DDX6 and 4E-T by using WAVE system with a KD of 774.3 nM. The compound inhibited PB formation that temporally increases during adipogenesis and epithelial-mesenchymal transition (EMT), and significantly suppressed their cellular transition. We also found that in the EMT model, the half-life of pre-existing mRNAs in PBs was extended twofold by the compound. The novel inhibitor of RNA decay will be not only a tool to analyze in detail what pathological conditions RNA decay affects and how it regulates the state, but also lead to drug discovery of the first in class as RNA decay inhibitor.
2022-06-01 | GSE196532 | GEO
Project description:An Affinity Purification (AP) step coupled with Proximity-dependent biotin ligation (PDL) reveals the proteome of Processing Bodies (PBs) in Arabidopsis.
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Project description:N6-Methyladenosine (m6A) is the predominant internal RNA modification in eukaryotic messenger RNAs (mRNAs) and plays a crucial role in mRNA stability. In this study, we reveal that m6A sites in the coding sequence (CDS) trigger CDS–m6A decay (CMD), a novel mRNA decay pathway that is distinct from previously reported m6A-dependent degradation mechanisms. Importantly, CDS m6A sites act considerably faster and more efficiently than those in the 3' untranslated region, which to date have been considered the main effectors of m6A-mediated RNA decay. Mechanistically, CMD depends on translation whereby m6A deposition in the CDS induces ribosome pausing and transcript destabilization. We found that the target transcripts of CMD are recognized by the m6A reader protein YTHDF2, selectively enriched in processing bodies (P-bodies) and degraded via the decapping factor DCP2. Our findings highlight CMD as a previously unknown pathway for m6A-mediated decay, which is particularly important for controlling the expression of developmental regulators and retrogenes.
2024-11-20 | GSE248574 | GEO
Project description:N6-Methyladenosine (m6A) is the predominant internal RNA modification in eukaryotic messenger RNAs (mRNAs) and plays a crucial role in mRNA stability. In this study, we reveal that m6A sites in the coding sequence (CDS) trigger CDS–m6A decay (CMD), a novel mRNA decay pathway that is distinct from previously reported m6A-dependent degradation mechanisms. Importantly, CDS m6A sites act considerably faster and more efficiently than those in the 3' untranslated region, which to date have been considered the main effectors of m6A-mediated RNA decay. Mechanistically, CMD depends on translation whereby m6A deposition in the CDS induces ribosome pausing and transcript destabilization. We found that the target transcripts of CMD are recognized by the m6A reader protein YTHDF2, selectively enriched in processing bodies (P-bodies) and degraded via the decapping factor DCP2. Our findings highlight CMD as a previously unknown pathway for m6A-mediated decay, which is particularly important for controlling the expression of developmental regulators and retrogenes.
2024-11-20 | GSE248572 | GEO
Project description:N6-Methyladenosine (m6A) is the predominant internal RNA modification in eukaryotic messenger RNAs (mRNAs) and plays a crucial role in mRNA stability. In this study, we reveal that m6A sites in the coding sequence (CDS) trigger CDS–m6A decay (CMD), a novel mRNA decay pathway that is distinct from previously reported m6A-dependent degradation mechanisms. Importantly, CDS m6A sites act considerably faster and more efficiently than those in the 3' untranslated region, which to date have been considered the main effectors of m6A-mediated RNA decay. Mechanistically, CMD depends on translation whereby m6A deposition in the CDS induces ribosome pausing and transcript destabilization. We found that the target transcripts of CMD are recognized by the m6A reader protein YTHDF2, selectively enriched in processing bodies (P-bodies) and degraded via the decapping factor DCP2. Our findings highlight CMD as a previously unknown pathway for m6A-mediated decay, which is particularly important for controlling the expression of developmental regulators and retrogenes.
2024-11-20 | GSE248571 | GEO
Project description:N6-Methyladenosine (m6A) is the predominant internal RNA modification in eukaryotic messenger RNAs (mRNAs) and plays a crucial role in mRNA stability. In this study, we reveal that m6A sites in the coding sequence (CDS) trigger CDS–m6A decay (CMD), a novel mRNA decay pathway that is distinct from previously reported m6A-dependent degradation mechanisms. Importantly, CDS m6A sites act considerably faster and more efficiently than those in the 3' untranslated region, which to date have been considered the main effectors of m6A-mediated RNA decay. Mechanistically, CMD depends on translation whereby m6A deposition in the CDS induces ribosome pausing and transcript destabilization. We found that the target transcripts of CMD are recognized by the m6A reader protein YTHDF2, selectively enriched in processing bodies (P-bodies) and degraded via the decapping factor DCP2. Our findings highlight CMD as a previously unknown pathway for m6A-mediated decay, which is particularly important for controlling the expression of developmental regulators and retrogenes.
2024-11-20 | GSE273217 | GEO
Project description:N6-Methyladenosine (m6A) is the predominant internal RNA modification in eukaryotic messenger RNAs (mRNAs) and plays a crucial role in mRNA stability. In this study, we reveal that m6A sites in the coding sequence (CDS) trigger CDS–m6A decay (CMD), a novel mRNA decay pathway that is distinct from previously reported m6A-dependent degradation mechanisms. Importantly, CDS m6A sites act considerably faster and more efficiently than those in the 3' untranslated region, which to date have been considered the main effectors of m6A-mediated RNA decay. Mechanistically, CMD depends on translation whereby m6A deposition in the CDS induces ribosome pausing and transcript destabilization. We found that the target transcripts of CMD are recognized by the m6A reader protein YTHDF2, selectively enriched in processing bodies (P-bodies) and degraded via the decapping factor DCP2. Our findings highlight CMD as a previously unknown pathway for m6A-mediated decay, which is particularly important for controlling the expression of developmental regulators and retrogenes.
2024-11-20 | GSE248573 | GEO
Project description:Signaling cascades during adipogenesis culminate in the expression of two essential adipogenic factors, PPARγ and C/EBPα. Here we demonstrate that the IRE1α-XBP1 pathway, the most conserved branch of the unfolded protein response (UPR), is indispensable for adipogenesis. Indeed, XBP1-deficient mouse embryonic fibroblasts and 3T3-L1 cells with XBP1 or IRE1α knockdown exhibit profound defects in adipogenesis. Intriguingly, C/EBPβ, a key early adipogenic factor, induces Xbp1 expression by directly binding to its proximal promoter region. Subsequently, XBP1 binds to the promoter of Cebpa and activates its gene expression. The posttranscriptional splicing of Xbp1 mRNA by IRE1α is required as only the spliced form of XBP1 (XBP1s) rescues the adipogenic defect exhibited by XBP1-deficient cells. Taken together, our data show that the IRE1α-XBP1 pathway plays a key role in adipocyte differentiation by acting as a critical regulator of the morphological and functional transformations during adipogenesis. The Xbp1 deficient MEFs are subjected to adipogenesis using standard drug induction. The cells are collected at day 0 and day 3. Total RNA are extracted from the cells and used for one channel microarray analysis. Expression levels on day 3 are compared to that on day 0.
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