Gene expression of blood cells in a patient with GATA2 deficiency.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE131372 | GEO | 2022/05/17
REPOSITORIES: GEO
Similar Datasets
Project description:Gene expression of blood cells in a patient with GATA2 deficiency.
| PRJNA543412 | ENA
Project description:Background and Purpose: Constitutional GATA2 deficiency caused by heterozygous germline GATA2 mutation has a broad spectrum of clinical phenotypes including systemic infections, lymphedema, cytopenias, MDS and AML. A comprehensive profiling of transcriptome of hematopoiesis in GATA2 deficiency is currently lacking. Methods: We performed single-cell RNA sequencing of sorted bone marrow CD34+ hematopoietic stem and progenitor cells (HSPCs) from eight GATA2 deficiency patients, who had various well characterized GATA2 mutations and clinically manifest myelodysplasia. We characterized transcriptomes in lineages, computationally defined cells with chromosomal abnormalities, and described gene expression of these cells. Results: Mapping patients’ cells onto normal hematopoiesis, we observed preferred deficiency in lymphoid and myeloid progenitors, which also was evidenced in loss of heterogeneity in gene correlations. HSPCs in patients exhibited distinct gene expression pattern and gene coexpression pattern compared with its counterparts in healthy donors. Distinct lineages show different transcriptional profiles resulting from GATA2 mutations. HSCs in patients exhibited dysregulated genes in apoptosis, cell cycle and quiescence, and had increased expression of erythroid/megakaryocytic priming programs and decreased lymphoid priming programs. Thus, the prominent deficiency in myeloid/lymphoid lineages in GATA2 deficiency was partly due to expression of aberrant gene programs in HSCs prior to lineage commitment. We computationally defined cells with chromosomal abnormalities and described gene expression of these cells. DNA repair genes were downregulated in trisomy 8 cells, possibly rendering these cells vulnerable to second-hit somatic mutations and additional chromosomal abnormalities. Cells with complex cytogenetics had defects in multi-lineage differentiation and cell cycle. Conclusion: Germline GATA2 mutations modulate gene expression and change gene coexpression patterns. Distinct lineages show different transcriptional profiles resulting from GATA2 mutations. The prominent deficiency in myeloid/lymphoid lineages in GATA2 deficiency was partly due to expression of aberrant gene programs in HSCs prior to lineage commitment.
2020-06-06 | GSE135194 | GEO
Project description:The majority (72%) of adolescents with myelodysplastic syndrome and monosomy 7 carry an underlying GATA2 deficiency. Nowadays, chemotherapy and allogenic hematopoietic stem cell transplantation (HSCT) are the only cure, pointing out the urgent need to develop reliable predictive tools. Familial cases carrying the same mutation in the GATA2 gene develop the disease at different age. The trigger of the disease is still unknown. Therefore, it is needed to understand the genetic mechanisms (mutations) and epigenetic mechanism, such as, DNA methylation, a cellular mechanism to control gene expression. Abnormal DNA methylation has been linked to several adverse outcomes, including human diseases. In this study, we deeply characterized 20 Spanish GATA2 deficient patients; study the presence of secondary mutations, clinical phenotype and DNA methylation. We have found that the most frequent secondary mutations are in STAG2 and ASXL1 genes, detected in 30% and 20% of the patients, respectively, a similar ratio has been described in a bigger cohort, showing that our 20-patient cohort is representative of the GATA2 deficiency scenario. For the first time, we found a specific hypermethylated signature in GATA2 patients, opening a novel point of view in the GATA2-patient diagnostic and facilitating the risk estimation of themselves. Furthermore, whether the methylation profiling is accurate enough, it will be useful to predict the onset of the disease progression.
2023-06-30 | E-MTAB-12551 | biostudies-arrayexpress
Project description:GATA2 Deficiency and the MonoMAC Syndrome
| PRJNA955848 | ENA
Project description:GATA2 Deficiency and the MonoMAC Syndrome
| PRJNA955837 | ENA
Project description:The majority (72%) of adolescents with myelodysplastic syndrome and monosomy 7 carry an underlying GATA2 deficiency. Nowadays, chemotherapy and allogenic hematopoietic stem cell transplantation (HSCT) are the only cure, pointing out the urgent need to develop reliable predictive tools. Familial cases carrying the same mutation in the GATA2 gene develop the disease at different age. The trigger of the disease is still unknown. Therefore, it is needed to understand the genetic mechanisms (mutations) and epigenetic mechanism, such as, DNA methylation, a cellular mechanism to control gene expression. Abnormal DNA methylation has been linked to several adverse outcomes, including human diseases. In this study, we deeply characterized 20 Spanish GATA2 deficient patients; study the presence of secondary mutations, clinical phenotype and DNA methylation. We have found that the most frequent secondary mutations are in STAG2 and ASXL1 genes, detected in 30% and 20% of the patients, respectively, a similar ratio has been described in a bigger cohort, showing that our 20-patient cohort is representative of the GATA2 deficiency scenario. For the first time, we found a specific hypermethylated signature in GATA2 patients, opening a novel point of view in the GATA2-patient diagnostic and facilitating the risk estimation of themselves. Furthermore, whether the methylation profiling is accurate enough, it will be useful to predict the onset of the disease progression.
2023-03-01 | GSE221745 | GEO
Project description:Typical features of GATA2 deficiency were observed in a individual with wild-type GATA2 sequence. The patient had a de novo tandem duplication of 187Kb spanning GATA2 and RPN1 containing a deletion of 25Kb 5’ of RPN1, inherited from the mother. The deletion is a copy number variant present in about 4% of Europeans (GRCh37: esv2725896 and nsv513733; GRCh38: esv3597711) and removes an alternative 5’ start site of RPN1 at 128,400Kb, associated with CTCF and H3K27ac binding peaks. A second copy of GATA2 is translocated to this region by the tandem duplication. RNA-Seq was underatken in order to identify any gene fussion events resulting from the mutation and to inverstigate differences in gene expression between the patient and controls.
2021-05-10 | GSE166201 | GEO
Project description:Transcriptional profiling of mouse comparing in vitro-derived DC progenitors from control and Gata2 conditional knockout mice. Two-condition experiment, Control DCs vs. G2 Knockout DCs. Biological replicates: 4 control, 3 Gata2 knockout, independently grown and harvested. One replicate per array. Dendritic cells (DCs) are critical immune response regulators; however, the mechanism of DC differentiation is not fully understood. Heterozygous germline GATA2 mutations induce GATA2 deficiency syndrome, characterized by monocytopenia, a predisposition to myelodysplasia/acute myeloid leukemia, and a profoundly reduced DC population, which is associated with increased susceptibility to viral infections, impaired phagocytosis, and decreased cytokine production. To define the role of GATA2 in DC differentiation and function, we studied Gata2 conditional knockout and haploinsufficient mice. Gata2 conditional deficiency significantly reduced the DC count, whereas Gata2 haploinsufficiency did not affect this population. GATA2 was required for the in vitro generation of DCs from Linâ??Sca-1+Kit+ cells, common myeloid-restricted progenitors, and common dendritic cell precursors, but not common lymphoid-restricted progenitors or granulocyte-macrophage progenitors, suggesting that GATA2 functions in the myeloid pathway of DC differentiation. Moreover, expression profiling demonstrated reduced expression of myeloid-related genes, including mafb, and increased expression of T-lymphocyte-related genes, including Gata3 and Tcf7, in Gata2-deficient DC progenitors. In addition, GATA2 was found to bind an enhancer element 190-kb downstream region of Gata3, and a reporter assay exhibited significantly reduced luciferase activity after adding this enhancer region to the Gata3 promoter, which was recovered by GATA sequence deletion within Gata3 +190. These results suggest that GATA2 plays an important role in cell fate specification toward the myeloid versus T lymphocyte lineage by regulating lineage-specific transcription factors in DC progenitors, thereby contributing to DC differentiation.
2016-05-31 | E-GEOD-82044 | biostudies-arrayexpress