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Reduced EIF6 dosage attenuates TP53 activation in models of Shwachman-Diamond syndrome

ABSTRACT: Reduced EIF6 dosage attenuates TP53 activation in models of Shwachman-Diamond syndrome

PROVIDER: PRJNA1188114 | ENA |

REPOSITORIES: ENA

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			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

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Reduced EIF6 dosage attenuates TP53 activation in models of Shwachman-Diamond syndrome

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.

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Reduced EIF6 dosage attenuates TP53 activation in models of Shwachman-Diamond syndrome.

Project description: Not available

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Repolarization of HSC attenuates HSCs failure in Shwachman-Diamond syndrome

Project description:Repolarization of HSC attenuates HSCs failure in Shwachman-Diamond syndrome

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Targeted Sequencing of Shwachman-Diamond syndrome bone marrow samples

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.

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Repolarization of HSC attenuates HSCs failure in Shwachman-Diamond syndrome

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.

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2021-06-18 | E-MTAB-9009 | biostudies-arrayexpress

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2026-02-10 | E-MTAB-14304 | biostudies-arrayexpress

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Project description:Analysis of the global variability of gene expression between the Eif6 WT control genotype and the Eif6 S235A mutated MEF lines. To analyze the effects over time of the lack of Eif6 phosphorylation, we transduced MEFs with tamoxifen-inducible Cre, so that treatment leads to excision of wild-type exons and the generation of cells bearing the S235A mutation. RNA-seq analyses were performed on samples collected at the time of tamoxifen addition (T0), 48 hours (T1), and 72 hours (T2) after the treatment.

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