Synergistic roles of DYRK1A and GATA1 in trisomy 21 megakaryopoiesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1019660 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26135217_1.fastq.gz | Fastqsanger.gz | |||
| SRR26135217_2.fastq.gz | Fastqsanger.gz | |||
| SRR26135218_1.fastq.gz | Fastqsanger.gz | |||
| SRR26135218_2.fastq.gz | Fastqsanger.gz | |||
| SRR26135219_1.fastq.gz | Fastqsanger.gz |
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Project description:Patients with Down syndrome (DS, trisomy 21, T21) are at increased risk of transient abnormal myelopoiesis (TAM) and acute megakaryoblastic leukemia (ML-DS). Both TAM and ML-DS require prenatal somatic mutations in GATA1, resulting in the truncated isoform GATA1s. The mechanism by which individual chromosome 21 (HSA21) genes synergize with GATA1s for leukemic transformation is challenging to study, in part due to limited human cell models with wild type GATA1 or GATA1s. HSA21-encoded DYRK1A is overexpressed in ML-DS and may be a therapeutic target. To determine how DYRK1A influences hematopoiesis in concert with GATA1s, we used gene editing to disrupt all 3 alleles of DYRK1A in isogenic T21 induced pluripotent stem cells (iPSCs) with and without the GATA1s mutation. Unexpectedly, hematopoietic differentiation revealed that DYRK1A loss combined with GATA1s leads to increased megakaryocyte proliferation and decreased maturation. This proliferative phenotype was associated with upregulation of D-type cyclins and hyperphosphorylation of Rb to allow E2F release and de-repression of its downstream targets. Notably, DYRK1A loss had no effect in T21/wtGATA1 megakaryocytes. These surprising results suggest that increased DYRK1A expression may be protective against TAM and ML-DS and that DYRK1A inhibition would not be a therapeutic option for GATA1s-associated leukemias.
2023-11-04 | GSE243702 | GEO
Project description:We generated human induced pluripotent stem cells (iPSCs) from trisomy 21 (T21) and euploid patient tissues with and without GATA1 mutations causing exclusive expression of truncated GATA1, termed GATA1short (GATA1s). Transcriptome analysis comparing expression levels of genes in GATA1s vs. wtGATA1-expressing progenitors demonstrated that GATA1s impairs erythropoiesis and enhances megakaryopoiesis and myelopoiesis in both T21 and euploid contexts in the iPSC-model system.
2015-01-26 | GSE36787 | GEO
Project description:We generated human induced pluripotent stem cells (iPSCs) from trisomy 21 (T21) and euploid patient tissues with and without GATA1 mutations causing exclusive expression of truncated GATA1, termed GATA1short (GATA1s). Transcriptome analysis comparing expression levels of genes in GATA1s vs. wtGATA1-expressing progenitors demonstrated that GATA1s impairs erythropoiesis and enhances megakaryopoiesis and myelopoiesis in both T21 and euploid contexts in the iPSC-model system. We analyzed the transcriptome of (i) T21 iPSC-derived heamtopoietic progenitors expressing wtGATA1 (6 replicates) or GATA1s (3 replicates), as well as of (ii) euploid iPSC-derived progenitors expressing wtGATA1 (2 replicates) or GATA1s (2 replicates).
2015-01-26 | E-GEOD-36787 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Germline GATA1 mutations resulting in the production of an amino-truncated protein termed GATA1s (for M-bM-^@M-^\shortM-bM-^@M-^]) cause congenital hypoplastic anemia. Similar somatic mutations promote transient myeloproliferative disease and acute megakaryoblastic leukemia in trisomy 21 patients. Here we show that induced pluripotent stem cells (iPSCs) from patients with GATA1-truncating mutations exhibit impaired erythroid potential but enhanced megakaryopoiesis and myelopoiesis, faithfully recapitulating the major phenotypes of associated diseases. Similarly, GATA1s promotes megakaryopoiesis but not erythropoiesis in developmentally arrested Gata1- murine megakaryocyte-erythroid progenitors derived from murine embryonic stem cells (ESCs). Transcriptome studies demonstrate a selective deficiency in the ability of GATA1s to activate erythroid-expressed genes within populations of hematopoietic progenitors. Although its DNA binding domain is intact, chromatin immunoprecipitation studies show that GATA1s binding at specific erythroid regulatory regions is impaired, while binding at many non-erythroid sites, including megakaryocytic and myeloid target genes, is normal. These observations point to lineage specific GATA1 co-factor associations essential for normal chromatin occupancy and provide mechanistic insights into how GATA1s mutations cause human disease. More broadly, our studies underscore the value of ESCs and iPSCs to recapitulate and study disease phenotypes. Refer to individual Series
2015-01-26 | E-GEOD-61933 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Germline GATA1 mutations resulting in the production of an amino-truncated protein termed GATA1s (for “short”) cause congenital hypoplastic anemia. Similar somatic mutations promote transient myeloproliferative disease and acute megakaryoblastic leukemia in trisomy 21 patients. Here we show that induced pluripotent stem cells (iPSCs) from patients with GATA1-truncating mutations exhibit impaired erythroid potential but enhanced megakaryopoiesis and myelopoiesis, faithfully recapitulating the major phenotypes of associated diseases. Similarly, GATA1s promotes megakaryopoiesis but not erythropoiesis in developmentally arrested Gata1- murine megakaryocyte-erythroid progenitors derived from murine embryonic stem cells (ESCs). Transcriptome studies demonstrate a selective deficiency in the ability of GATA1s to activate erythroid-expressed genes within populations of hematopoietic progenitors. Although its DNA binding domain is intact, chromatin immunoprecipitation studies show that GATA1s binding at specific erythroid regulatory regions is impaired, while binding at many non-erythroid sites, including megakaryocytic and myeloid target genes, is normal. These observations point to lineage specific GATA1 co-factor associations essential for normal chromatin occupancy and provide mechanistic insights into how GATA1s mutations cause human disease. More broadly, our studies underscore the value of ESCs and iPSCs to recapitulate and study disease phenotypes.
2015-01-26 | GSE61933 | GEO
Project description:ETS2, ERG promote megakaryopoiesis, synergize with alterations in GATA1 to immortalize hematopoietic progenitor cells
| PRJNA111647 | ENA
Project description:Down Syndrome (DS) results from the trisomy of human chromosome 21 (HSA21). It is still the most frequent intellectual disability, affecting 1 newborn per 700 births. Among candidate genes explaining intellectual disabilities seen in DS patients, the dual specificity tyrosine-phosphorylation regulated kinase 1A, DYRK1A, is located in the DS critical region of chromosome 21. DYRK1A has become a major screening target for the development of selective and potent pharmacological inhibitors. We here investigated the effects of a relatively selective DYRK1A inhibitor, Leucettine 41 (hereafter L41) in three different trisomic mouse models with increasing genetic complexity, Tg(Dyrk1a), Ts65Dn and Dp1Yey. Leucettines are derived from the marine sponge alkaloid Leucettamine B.
2018-10-17 | PXD008419 | Pride
Project description:Thioredoxin-interacting protein (TXNIP) is ubiquitously expressed in blood cells, including hematopoietic stem cells (HSCs), monocytes, and platelets. Here we report a novel finding that TXNIP plays a crucial role in megakaryopoiesis and platelet biogenesis via interacting with GATA1, a transcription factor for megakaryocyte-erythroid differentiation. Txnip-/- mice displayed immature megakaryocytes in the bone marrow with thrombocytopenia, which had gotten worse as the mice aged. Transcriptome analysis revealed that the transcriptional activity of GATA1 was significantly enhanced in the Txnip-/- megakaryocyte precursors (MkPs) than wild type (WT) cells. During megakaryopoiesis in ex vivo, Txnip-/- MkPs remained small in cell size with less mitochondrial mass, and more glycolysis for ATP production, as opposed to the normal megakaryocyte maturation. The effects of TXNIP in megakaryocytes were recapitulated in human cord blood CD34+ HSC-derived differentiation. Taken together, this study demonstrates the importance of spatiotemporal expression of TXNIP in platelet biogenesis. We propose for the first time that TXNIP might play a critical role in determining a lineage between megakaryocytes and erythroid cells from a common megakaryocyte-erythroid progenitor via regulation of transcriptional activity of GATA1.
2022-12-31 | GSE186400 | GEO
Project description:DYRK1A is a protein kinase with several roles in brain development. This kinase is involved in two intellectual disability syndromes: Down syndrome and DYRK1A haploinsufficiency syndrome. The Dyrk1a+/- mouse is a model for DYRK1A haploinsufficiency syndrome. We used microarray to evaluate the impact of DYRK1A haploinsufficiency in the development of the cerebral cortex.
2019-03-06 | GSE127707 | GEO
Project description:Transcription profiling of transgenic down syndrome mouse model to show the role of DYRK1A gene. The molecular mechanisms that lead to the cognitive defects characteristic of Down syndrome (DS), the most frequent cause of mental retardation, have remained elusive. Here we use a transgenic DS mouse model to show that DYRK1A gene dosage imbalance deregulates chromosomal clusters of genes located near neuron-restrictive silencer factor (REST/NRSF) binding sites. We found that DYRK1A binds the SWI/SNF-complex known to interact with REST/NRSF. Mutation of a REST/NRSF binding site in the promoter of the REST/NRSF target gene L1cam modifies the transcriptional effect of Dyrk1Adosage imbalance on L1cam. DyrkA dosage imbalance perturbs Rest/Nrsf levels with decreased Rest/Nrsf expression in embryonic neurons and increased expression in adult neurons. We identified a coordinated deregulation of multiple genes that are responsible for the cellular phenotypic traits present in DS such as dendritic growth impairment and microcephaly during prenatal cortex development. Dyrk1a overexpression in primary mouse cortical neurons reduced the neuritic complexity. In the postnatal hippocampus, DYRK1A overexpression suppresses a form of synaptic plasticity that may be sufficient to cause DS cognitive defects. We propose that DYRK1A overexpression-related neuronal gene deregulation generates the brain phenotypic changes that characterize DS, with an accessory role for the gene dosage imbalance of other chromosome 21 genes. Transgenic embrionic brain regions versus wild type mice were analysed. The log2 values represent Cy5/Cy3 ratio (transgenic Cy5/wild type Cy3). Each array was scanned under a green laser (543 nm for Cy3 labeling) or a red laser (633 nm for Cy5 labeling) using a ScanArray Lite scanning confocal fuorescent scanner with 10 u resolution (laser power: 85% for Cy5 and 90% for Cy3, gain: 75% for Cy5 and 70% for Cy3). Scanned output files were analyzed using the GenePix Pro 3.0 software. Each spot was defined by automatic positioning of a grid of circles over the image. The average and median pixel intensity ratios calculated from both channels and the local background of each spot were determined. Local background corrected intensity ratios was determined for each spot. The background-corrected expression data were filtered for flagged spots and weak signal. Normalization was performed by the global Lowess method. Studentâs t-test was applied to determine the p value.
2010-05-05 | E-GEOD-14072 | biostudies-arrayexpress