Reduced EIF6 dosage attenuates TP53 activation in models of Shwachman-Diamond syndrome
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1188114 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31399561_1.fastq.gz | Fastqsanger.gz | |||
| SRR31399561_2.fastq.gz | Fastqsanger.gz | |||
| SRR31399562_1.fastq.gz | Fastqsanger.gz | |||
| SRR31399562_2.fastq.gz | Fastqsanger.gz | |||
| SRR31399563_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
Similar Datasets
Project description:Shwachman-Diamond syndrome (SDS) is characterized by neutropenia, exocrine pancreatic insufficiency, and bony abnormalities with an increased risk of myeloid neoplasia. Almost all cases of SDS result from biallelic mutations in SBDS. SBDS interacts with EFL1 to displace EIF6 from the 60S ribosomal subunit. Released EIF6 permits the assembly of ribosomal large and small subunits in the cytoplasm. Decreased EIF6 levels due to haploinsufficiency or missense mutations which lead to decreased protein expression may provide a somatic genetic rescue and anti-leukemic effects. We observed accumulation of EIF6 protein in sbds knockout (KO) zebrafish models, confirmed in patient-derived tissues, and correlated with changes in ribosome proteins and TP53 pathways. The mechanism of action for this adaptive response is unknown. To address this, we generated an eif6 zebrafish KO line which do not survive past 10 days post fertilization. We also created two mutants with low Eif6 expression, 5-25% of the wildtype levels, that can survive until adulthood. We bred them with sbds-null strains and analyzed their phenotype and biochemical properties. Low Eif6 levels reduced Tp53 pathway activation but did not rescue neutropenia in Sbds-deficient zebrafish. Further studies elucidating the interplay between SBDS, EIF6, TP53, and cellular stress responses offer promising insights into SDS pathogenesis, somatic genetic rescue, and therapeutic strategies.
2025-04-01 | GSE282310 | GEO
Project description:Repolarization of HSC attenuates HSCs failure in Shwachman-Diamond syndrome
| PRJNA664115 | ENA
Project description:Targeted sequencing of myeloid malignancy-associated genes as well as EIF6 in bone marrow samples in Shwachman-Diamond syndrome patients. Paired bone marrow fibroblasts serve as a germline control.
| EGAS00001004879 | EGA
Project description:A cohort of age-matched mice (eIF6+/+ and eIF6+/-) were fed with High-Fat Diet. All experimental mice were sacrificed after 16 weeks and the livers were recovered. RNA was isolated from liver biopsies of eIF6+/+ and eIF6+/- mice and RNAseq analysis was performed. The aim of the analysis is the investigation of the transcriptional changes driven by chronic depletion of eIF6 in the liver of mice upon High Fat Diet (HFD) feeding.
2021-06-18 | E-MTAB-9009 | biostudies-arrayexpress
Project description:Shwachman-Diamond syndrome (SDS) is a bone marrow failure (BMF) syndrome associated with an increased risk of myelodysplasia and leukemia. The molecular mechanisms of SDS are not fully understood. We report that primitive hematopoietic cells from SDS patients present with a reduced activity of the small Rho GTPase Cdc42 and concomitantly a reduced frequency of HSCs polar for polarity proteins. The level of apolarity of SDS HSCs correlated with the magnitude of HSC depletion in SDS patients. Importantly, exogenously provided Wnt5a or GDF11 that elevates the activity of Cdc42 restored polarity in SDS HSCs and increased the number of HSCs in SDS patient samples in surrogate ex vivo assays. Single cell level RNA-Seq analyses of SDS HSCs and daughter cells demonstrated that SDS-HSC treated with GDF11 are transcriptionally more similar to control than to SDS-HSCs. Treatment with GDF11 reverted pathways in SDS HSCs associated with rRNA processing and ribosome function, but also viral infection and immune function, p53-dependent DNA damage, spindle checkpoints, and metabolism, further implying a role of these pathways in HSC failure in SDS. Our data suggest that HSC failure in SDS is driven at least in part by low Cdc42 activity in SDS HSCs. Our data thus identify novel rationale approaches to attenuate HSCs failure in SDS.
2020-09-18 | GSE158140 | GEO
Project description:Despite the advanced understanding of disease mechanisms, the current therapeutic regimens fail to cure most patients with acute myeloid leukemia (AML). In the present study, we address the role of protein synthesis control in leukemia function and leukemia propagation. Using a transgenic eIF6 mouse strain that permits inducible and graded regulation of ribosomal subunit joining, we have generated a murine model of MLL-AF9 acute myeloid leukemia where the expression of transgenic eIF6 is doxycycline-inducible. Using this model system, we have performed scRNA-seq expression analysis to study the impact of eIF6 overexpression on leukemia cell function. scRNA-seq was performed using the 10x Chromium Next GEM Single Cell 3ʹ platform. BM cells were harvested from leukemia-engrafted mice that were administered doxycycline for six days and viable GFP+ leukemia cells were sorted into PBS containing 0.05 % BSA following the manusfacturer’s protocol. 5 samples: 2 control and 3 eIF6 overexpression.
2024-10-10 | E-MTAB-13567 | biostudies-arrayexpress
Project description:Tibialis anterior and gastrocnemius muscle from Eif6 heterozygous mice and wild-type mice profiled using Agilent gene expression arrays
2018-07-07 | GSE116709 | GEO
Project description:Soleus muscle from Eif6 heterozygous mice and wild-type mice profiled using Agilent gene expression arrays
2018-07-07 | GSE116714 | GEO
Project description:Moderating the pool of active ribosomal subunits is critical for maintaining global translation rates. A crucial factor for modulating the 60S ribosomal subunits is eukaryotic translation initiation factor 6. Release of eIF6 from 60S is essential to permit 60S interactions with 40S. Here, using the N106S mutant of eIF6, we show that disrupting eIF6 interaction with 60S leads to an increase in vacant 80S. It further highlights a dichotomy in the anti-association activity of eIF6 that is distinct from its role in 60S biogenesis and shows that the nucleolar localization of eIF6 is not dependent on uL14-BCCIP interactions. Limiting active ribosomal pools markedly deregulates translation especially in mitosis and leads to chromosome segregation defects, mitotic exit delays and mitotic catastrophe. Ribo-Seq analysis of the eIF6-N106S mutant shows a significant downregulation in the translation efficiencies of mitotic factors and specifically transcripts with long 3′UTRs. eIF6-N106S mutation also limits cancer invasion, and this role is correlated with the overexpression of eIF6 only in high-grade invasive cancers suggesting that deregulation of eIF6 is probably not an early event in cancers. Thus, this study highlights the segregation of eIF6 functions and its role in moderating 80S availability for mitotic translation and cancer progression.
2024-12-04 | GSE272516 | GEO
Project description:Moderating the pool of active ribosomal subunits is critical for maintaining global translation rates. A crucial factor for modulating the 60S ribosomal subunits is eukaryotic translation initiation factor 6. Release of eIF6 from 60S is essential to permit 60S interactions with 40S. Here, using the N106S mutant of eIF6, we show that disrupting eIF6 interaction with 60S leads to an increase in vacant 80S. It further highlights a dichotomy in the anti-association activity of eIF6 that is distinct from its role in 60S biogenesis and shows that the nucleolar localization of eIF6 is not dependent on uL14-BCCIP interactions. Limiting active ribosomal pools markedly deregulates translation especially in mitosis and leads to chromosome segregation defects, mitotic exit delays and mitotic catastrophe. Ribo-Seq analysis of the eIF6-N106S mutant shows a significant downregulation in the translation efficiencies of mitotic factors and specifically transcripts with long 3′UTRs. eIF6-N106S mutation also limits cancer invasion, and this role is correlated with the overexpression of eIF6 only in high-grade invasive cancers suggesting that deregulation of eIF6 is probably not an early event in cancers. Thus, this study highlights the segregation of eIF6 functions and its role in moderating 80S availability for mitotic translation and cancer progression.
2024-12-04 | GSE272515 | GEO