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Global translation during early development depends on the essential transcription factor PRDM10 [RNA-seq]

ABSTRACT: Members of the PR/SET domain-containing (PRDM) family of zinc finger transcriptional regulators play diverse roles in embryonic development and lineage differentiation. PRDM10 is a yet uncharacterized family member, with unknown functions in vivo. Here we report an essential requirement for PRDM10 in the pre-implantation embryo and embryonic stem cells (mESCs), where loss of PRDM10 results in severe cell growth inhibition. Genomic and biochemical analyses reveal that PRDM10 functions as a sequence-specific transcription factor which modulates gene expression by binding to target gene promoters. We identify Eif3b, which encodes a core component of the eukaryotic translation initiation factor 3 (eIF3) complex, as a key downstream target and demonstrate that growth inhibition in PRDM10-deficient mESCs is largely mediated through EIF3B-dependent effects on global translation. This work elucidates the molecular function of PRDM10 in maintaining global translation and establishes its essential role in early embryonic development and mESC homeostasis, offering novel insights into the functional repertoire of PRDMs as well as the transcriptional mechanisms regulating global translation.

ORGANISM(S): Mus musculus

PROVIDER: GSE135021 | GEO | 2020/05/06

REPOSITORIES: GEO

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Global translation during early development depends on the essential transcription factor PRDM10 [RNA-Seq_2]

Project description:Members of the PR/SET domain-containing (PRDM) family of zinc finger transcriptional regulators play diverse roles in embryonic development and lineage differentiation. PRDM10 is a yet uncharacterized family member, with unknown functions in vivo. Here we report an essential requirement for PRDM10 in the pre-implantation embryo and embryonic stem cells (mESCs), where loss of PRDM10 results in severe cell growth inhibition. Genomic and biochemical analyses reveal that PRDM10 functions as a sequence-specific transcription factor which modulates gene expression by binding to target gene promoters. We identify Eif3b, which encodes a core component of the eukaryotic translation initiation factor 3 (eIF3) complex, as a key downstream target and demonstrate that growth inhibition in PRDM10-deficient mESCs is largely mediated through EIF3B-dependent effects on global translation. This work elucidates the molecular function of PRDM10 in maintaining global translation and establishes its essential role in early embryonic development and mESC homeostasis, offering novel insights into the functional repertoire of PRDMs as well as the transcriptional mechanisms regulating global translation.

2020-05-06 | GSE142600 | GEO

Global translation during early development depends on the essential transcription factor PRDM10 [ChIP-seq]

2020-05-06 | GSE135020 | GEO

Nat1 promotes translation of specific proteins that induce differentiation of mouse embryonic stem cells [expression 2]

Project description:Nat1 (also known as p97/Dap5/Eif4g2) is a ubiquitously expressed cytoplasmic protein that is homologous to the c-terminal two thirds of eukaryotic translation initiation factor 4G (also known as Eif4g1). We previously showed that Nat1-null mouse embryonic stem cells (mESCs) were resistant to differentiation. In the current study, we found that NAT1 and eIF4G1 share many binding proteins, such as eIF3, eIF4A and ribosomal proteins. However, NAT1did not bind to eIF4E or poly A binding proteins, which are critical for cap-dependent translation initiation. In contrast, compared to eIF4G1, NAT1 preferentially interacts with eIF2, FMR and related proteins, and especially PRRC2 family members. We also found that Nat1-null mESCs possess a transcriptional profile similar, though not identical, to ground state, which is established in wild-type mES cells when treated with inhibitors of the ERK and GSK3 signaling pathways. In Nat1-null mESCs, the ERK pathway is suppressed even without inhibitors. Ribosome profiling revealed that translation of Map3k3 and Sos1 is suppressed in the absence of Nat1. Forced expression of Map3k3 induced differentiation of Nat1-null mESCs. These data collectively showed that Nat1 is involved in translation of proteins that are required for cell differentiation.

2017-01-06 | GSE89600 | GEO

EIF3B knockdown

Project description:Eukaryotic translation initiation factor 3B (EIF3B) knockdown in SMMC-7721 cells EIF3B vs. Scramble siRNA

2015-04-07 | E-GEOD-67594 | biostudies-arrayexpress

Controlling tissue patterning by translational regulation of signaling transcripts through the core translation factor eIF3c [II]

Project description:Although gene expression is tightly regulated during embryonic development, the impact of translational control has received less experimental attention. Here, we find that eukaryotic translation initiation factor-3 (eIF3) is required for Shh-mediated tissue patterning. Analysis of loss-of-function eIF3 subunit c (Eif3c) mice reveal a unique sensitivity to the Shh receptor Patched 1 (Ptch1) dosage. Genome-wide in vivo enhanced cross-linking immunoprecipitation sequence (eCLIP-seq) shows unexpected specificity for eIF3 binding to a pyrimidine rich motif present in subsets of 5’-UTRs and a corresponding change in the translation of these transcripts by ribosome profiling in Eif3c loss-of-function embryos. We further find that while Eif3c loss-of-function embryos do not show a global decrease in protein synthesis, translation of Ptch1 through this pyrimidine rich motif is specifically sensitive to eIF3 amount. Altogether, this work uncovers hidden specificity of housekeeping translation initiation machinery for the translation of key developmental signaling transcripts.

2021-09-30 | GSE183471 | GEO

Controlling tissue patterning by translational regulation of signaling transcripts through the core translation factor eIF3c [I]

2021-09-30 | GSE183470 | GEO

eIF3B CLIP-sequencing in prostate cancer

Project description:The role of eIF3B in advanced therapy resistant lethal stages of prostate cancer remains unknown. To gain insight into how eIF3B regulates the translation of specific mRNAs we performed Genome-wide eIF3B enhanced cross-linking immunoprecipitation sequencing (eCLIP-seq). this analysis showed specialized binding to a UC-rich motif present in subsets of 5’-UTRs. Indeed, translation of the androgen receptor (AR) and major histocompatibility complex I (MHC-I) through this motif are sensitive to eIF3B amount. These results suggest that eIF3B by regulating specific mRNA translation may play key role in the pathogenesis of lethal prostate cancer.

2023-12-22 | GSE240338 | GEO

EIF3B knockdown

Project description:Eukaryotic translation initiation factor 3B (EIF3B) knockdown in SMMC-7721 cells

2015-04-07 | GSE67594 | GEO

m6A in 5â untranslated regions promotes cap-independent translation of mRNA

Project description:N6-methyladenosine (m6A) is a widespread internal RNA modification whose function is poorly understood. Here we report that m6A residues within the 5'UTR promote a novel form of cap-independent translation which is mediated through an interaction between m6A residues and the translation initiation factor, eIF3. We present eIF3a PAR-iCLIP data which demonstrate that eIF3 predominantly binds mRNAs within the 5'UTR. eIF3 binding sites are also in proximity to m6A residues within the 5'UTR of cellular mRNAs. Two replicates of eIF3a PAR-iCLIP in HEK293T cells.

2015-10-26 | E-GEOD-73405 | biostudies-arrayexpress

eIF3 Engages with 3’-UTR Termini of Highly Translated mRNAs in Neural Progenitor Cells [APA-Seq]

Project description:Stem cell differentiation involves a global increase in protein synthesis to meet the demands of specialized cell types. However, the molecular mechanisms underlying this translational burst and the involvement of initiation factors remains largely unknown. Here, we investigate the roles of eukaryotic initiation factor 3 (eIF3) in early differentiation of human pluripotent stem cell (hPSC)-derived neural progenitor cells (NPCs). Using Quick-irCLIP and alternative polyadenylation (APA)-Seq, we show eIF3 crosslinks to many neurologically relevant mRNAs in NPCs. Our data reveal eIF3 predominantly interacts with 3’ untranslated region (3’-UTR) termini of multiple mRNA isoforms, adjacent to the poly(A) tail. High eIF3 crosslinking at 3’-UTR termini of mRNAs correlates with high translational activity, as determined by ribosome profiling. We identify the transcriptional regulator inhibitor of DNA binding 2 (ID2) mRNA as a case in which active translation levels and eIF3 crosslinking are dramatically increased upon early NPC differentiation. Furthermore, we find that eIF3 engagement at 3’-UTR ends is dependent on polyadenylation. The results presented here show that eIF3 engages with 3’-UTR termini in highly translated mRNAs, supporting a role of mRNA circularization in the mechanisms governing mRNA translation in NPCs.

2023-12-08 | GSE246786 | GEO

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