Investigating DDX41's Functional Role in Erythroid G-Quadruplex Dissolution
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ABSTRACT:
PROVIDER: PRJNA1068623 | ENA |
REPOSITORIES: ENA
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Project description:To explore the functional role of DDX41 in the dissolution of G-quadruplexes, we conducted Cut&Run assays in both mouse erythroid cells and hematopoietic stem and progenitor cells (HSPCs). Initially, we harvested mouse bone marrow cells through PBS flushing. Subsequently, we isolated erythroid cells using Ter119 antibodies and purified HSPCs by selectively collecting lineage-negative cells. These cells were then subjected to Cut&Run assays, utilizing DDX41 antibodies and Bg4 antibodies. The DNA fragments obtained through this process were sonicated and sent for sequencing and subsequent analysis via NUseq.
2025-08-13 | GSE254143 | GEO
Project description:Most cases of adult myeloid neoplasms are routinely assumed to be sporadic. Here, we describe an adult familial acute myeloid leukemia (AML) syndrome caused by germline mutations in the DEAD/H-Box helicase gene DDX41. DDX41 was also found to be affected by somatic mutations in sporadic cases of myeloid neoplasms as well as in a biallelic fashion in 50% of patients with germline DDX41 mutations. Moreover, corresponding deletions on 5q35.3 present in 6% of cases lead to haploinsufficient DDX41 expression. DDX41 lesions caused altered pre-mRNA splicing and RNA processing. DDX41 is exemplary of other RNA helicase genes also affected by somatic mutations, suggesting that they constitute a family of tumor suppressor genes. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from cryopreserved diagnostic bone marrow or peripheral blood samples.
2015-04-01 | E-GEOD-66668 | biostudies-arrayexpress
Project description:Purpose: Investigating transcriptome changes after depletion of DDX41. Methods: mRNA profiles after DDX41 knockdown compared to control knockdown were generated in 5 biological replicates. Samples were mapped using STAR (v2.7) against hg38 with the Gencode annotation. Reads per gene were counted using featureCounts (v.1.6). The differential expression analysis was performed using Bioconductor (v2.46)/DESeq2 (v1.26). Genes were deemed sign. diff. regulated with an FDR below 1% Results: We were able to map 32,705 transcripts. Reactome pathway analysis revealed members of the NOTCH and TGFß family to be significantly upregulated when comparing a control knockdown to DDX41 knockdown. In addition, genes in chromatin organization were upregulated.
2021-05-04 | GSE168171 | GEO
Project description:Germline heterozygous mutations in DDX41 predispose individuals to hematologic malignancies in adulthood. Most of these DDX41 mutations result in a truncated protein, leading to loss of protein function. To investigate the impact of these mutations on hematopoiesis, we generated mice with hematopoietic-specific knockout of one Ddx41 allele. Under normal steady-state conditions, there was minimal effect on lifelong hematopoiesis, resulting in a mild yet persistent reduction in red blood cell counts. However, stress induced by transplantation of the Ddx41+/- BM resulted in hematopoietic stem/progenitor cell (HSPC) defects and onset of hematopoietic failure upon aging. Transcriptomic analysis of HSPC subsets from the transplanted BM revealed activation of cellular stress responses, including upregulation of p53 target genes in erythroid progenitors. To understand how the loss of p53 affects the phenotype of Ddx41+/- HSPCs, we generated mice with combined Ddx41 and Trp53 heterozygous deletions. The reduction in p53 expression rescued the fitness defects in HSPC caused by Ddx41 heterozygosity. However, the combined Ddx41 and Trp53 mutant mice were prone to developing hematologic malignancies that resemble human myelodysplastic syndrome and acute myeloid leukemia. In conclusion, DDX41 heterozygosity causes dysregulation of the response to hematopoietic stress, which increases the risk of transformation with a p53 mutation.
2024-06-13 | GSE247408 | GEO
Project description:Germline heterozygous mutations in DDX41 predispose individuals to hematologic malignancies in adulthood. Most of these DDX41 mutations result in a truncated protein, leading to loss of protein function. To investigate the impact of these mutations on hematopoiesis, we generated mice with hematopoietic-specific knockout of one Ddx41 allele. Under normal steady-state conditions, there was minimal effect on lifelong hematopoiesis, resulting in a mild yet persistent reduction in red blood cell counts. However, stress induced by transplantation of the Ddx41+/- BM resulted in hematopoietic stem/progenitor cell (HSPC) defects and onset of hematopoietic failure upon aging. Transcriptomic analysis of HSPC subsets from the transplanted BM revealed activation of cellular stress responses, including upregulation of p53 target genes in erythroid progenitors. To understand how the loss of p53 affects the phenotype of Ddx41+/- HSPCs, we generated mice with combined Ddx41 and Trp53 heterozygous deletions. The reduction in p53 expression rescued the fitness defects in HSPC caused by Ddx41 heterozygosity. However, the combined Ddx41 and Trp53 mutant mice were prone to developing hematologic malignancies that resemble human myelodysplastic syndrome and acute myeloid leukemia. In conclusion, DDX41 heterozygosity causes dysregulation of the response to hematopoietic stress, which increases the risk of transformation with a p53 mutation.
2024-06-13 | GSE247404 | GEO
Project description:Germline heterozygous mutations in DDX41 predispose individuals to hematologic malignancies in adulthood. Most of these DDX41 mutations result in a truncated protein, leading to loss of protein function. To investigate the impact of these mutations on hematopoiesis, we generated mice with hematopoietic-specific knockout of one Ddx41 allele. Under normal steady-state conditions, there was minimal effect on lifelong hematopoiesis, resulting in a mild yet persistent reduction in red blood cell counts. However, stress induced by transplantation of the Ddx41+/- BM resulted in hematopoietic stem/progenitor cell (HSPC) defects and onset of hematopoietic failure upon aging. Transcriptomic analysis of HSPC subsets from the transplanted BM revealed activation of cellular stress responses, including upregulation of p53 target genes in erythroid progenitors. To understand how the loss of p53 affects the phenotype of Ddx41+/- HSPCs, we generated mice with combined Ddx41 and Trp53 heterozygous deletions. The reduction in p53 expression rescued the fitness defects in HSPC caused by Ddx41 heterozygosity. However, the combined Ddx41 and Trp53 mutant mice were prone to developing hematologic malignancies that resemble human myelodysplastic syndrome and acute myeloid leukemia. In conclusion, DDX41 heterozygosity causes dysregulation of the response to hematopoietic stress, which increases the risk of transformation with a p53 mutation.
2024-06-13 | GSE247403 | GEO
Project description:Most cases of adult myeloid neoplasms are routinely assumed to be sporadic. Here, we describe an adult familial acute myeloid leukemia (AML) syndrome caused by germline mutations in the DEAD/H-Box helicase gene DDX41. DDX41 was also found to be affected by somatic mutations in sporadic cases of myeloid neoplasms as well as in a biallelic fashion in 50% of patients with germline DDX41 mutations. Moreover, corresponding deletions on 5q35.3 present in 6% of cases lead to haploinsufficient DDX41 expression. DDX41 lesions caused altered pre-mRNA splicing and RNA processing. DDX41 is exemplary of other RNA helicase genes also affected by somatic mutations, suggesting that they constitute a family of tumor suppressor genes.
2015-04-01 | GSE66668 | GEO
Project description:The purpose of the experiment was to define the gene expression and splicing alterations occurring when the levels of dead-box helicase 41 are lowered in embryonic zebrafish. Results provide insight the role of Ddx41 in hematopoietic development.
2021-06-30 | GSE160979 | GEO
Project description:Genetic expression profiling (GEP) has previously proven useful in B-ALL for identifying signatures of oncogenes, with the recognition of novel subgroups, as well as with outcome. Therefore, we adopted GEP of bonemarrow samples of B-ALL with t(9;22) to uncover the contribution of DDX41 to leukemogenesis. The germline mutations of DDX41, also known as DEAD box RNA helicase 41, have been found in about 1.5% of myeloid neoplasms (MNs). Development of MDS/AML is relatively common in germline DDX41 mutations. However, a variety of hematological malignancies (HMs) have been reported. We report a novel case of bi-alleleic DDX41 mutations in B-cell lymphoblastic leukemia (B-ALL), with unusual location of DDX41 mutations. The gene expression profile (GEP) of Ph+ B-ALL with bi-alleleic DDX41 mutations showed heterogeneously transitional GEP and altered gene expression levels of genes involved in the process essential for red blood cells and myeloid cell differentiation were noted. We report that DDX41 mutations are unusual but can be an underlying event in Ph+B-ALL and screening DDX41 mutations can be also informative for patients awaiting for haploidentical stem cell transplantation and choosing the therapy.
2022-02-07 | GSE196107 | GEO
Project description:DDX41, a member of the DEXDc family of helicases and an innate immune protein, senses cytosolic DNA and bacterial secondary messengers and initiates signaling via the adaptor STING to induce type 1 interferon (IFN) response in dendritic cells. However, DDX41 function in tumor progression is poorly understood. Here we found that the DDX41 inhibited proliferation and promoted apoptosis, reported the whole transcriptome profiling in HeLa cells. RNA-seq analyses revealed that the overexpression of DDX41 resulted in 959 genes being differentially expressed (504 up-regulated and 455 down-regulated) compared to the control in HeLa cells. Interestingly, functional clustering pathway enrichment analysis of transcription identified antigen processing and presentation pathways were significantly activated in DDX41 overexpression samples, but alternative splicing enriched in the epidermal growth factor receptor signaling pathway and fibroblast growth factor receptor signaling pathway. The five antigen processing and processing genes, which could regulate cross-presentation of antigens and protective antitumor immune responses, were significantly upregulated, suggesting DDX41 is the key player in tumor immunity. In conclusion, our RNA-seq data identified molecules and pathways involved in the mechanisms of DDX41 that adds to the understanding of critical DDX41 tumorigenesis functions.
2021-02-10 | GSE122986 | GEO