Gata2 loss alters epigenetic priming and gene expression profiles in early myeloid and lymphoid progenitors leading to cytopenias
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ABSTRACT:
PROVIDER: PRJNA635158 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11851828.fastq.gz | Fastqsanger.gz | |||
| SRR11851828_1.fastq.gz | Fastqsanger.gz | |||
| SRR11851828_2.fastq.gz | Fastqsanger.gz | |||
| SRR11851829_1.fastq.gz | Fastqsanger.gz | |||
| SRR11851829_2.fastq.gz | Fastqsanger.gz |
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Project description:Germline heterozygous mutations in GATA2 are associated with a syndrome characterized by cytopenias, atypical infections, and increased risk of hematologic malignancies. Due to embryonic lethality of Gata2-/- mice, the role of germline loss of GATA2 has not been studied in adult hematopoiesis. Here, we generated a zebrafish mutant of gata2b, which in adulthood recapitulated the myelomonocytopenia and B cell lymphopenia of GATA2 syndrome. Using single cell epigenetic and transcriptomic analyses, we showed that loss of gata2b alters chromosome accessibility and results in gene expression changes in both early myeloid and lymphoid progenitors. We found differentiation block with skewing away from the monocytic program in myeloid progenitors in gata2bko zebrafish. In lymphoid progenitors, gata2b loss led to increased lymphoid priming but with incomplete B cell lymphopoiesis. These results place GATA2 in critical junctions of lineage specification in adult hematopoiesis.
2021-02-25 | GSE151231 | GEO
Project description:Germline heterozygous mutations in GATA2 are associated with a syndrome characterized by cytopenias, atypical infections, and increased risk of hematologic malignancies. Due to embryonic lethality of Gata2-/- mice, the role of germline loss of GATA2 has not been studied in adult hematopoiesis. Here, we generated a zebrafish mutant of gata2b, which in adulthood recapitulated the myelomonocytopenia and B cell lymphopenia of GATA2 syndrome. Using single cell epigenetic and transcriptomic analyses, we showed that loss of gata2b alters chromosome accessibility and results in gene expression changes in both early myeloid and lymphoid progenitors. We found differentiation block with skewing away from the monocytic program in myeloid progenitors in gata2bko zebrafish. In lymphoid progenitors, gata2b loss led to increased lymphoid priming but with incomplete B cell lymphopoiesis. These results place GATA2 in critical junctions of lineage specification in adult hematopoiesis.
2021-02-25 | GSE151230 | GEO
Project description:Gata2 loss alters epigenetic priming and gene expression profiles in early myeloid and lymphoid progenitors leading to cytopenias [RNA-seq]
| PRJNA635161 | ENA
Project description:Gata2 loss alters epigenetic priming and gene expression profiles in early myeloid and lymphoid progenitors leading to cytopenias [ATAC-seq]
| PRJNA635160 | 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:This SuperSeries is composed of the SubSeries listed below.
2021-02-25 | GSE151232 | GEO
Project description:Hematopoietic stem cells (HSCs) must balance self-renewal and lineage differentiation to regenerate the hematopoietic system throughout life. HSCs exhibit lineage-associated gene expression that keeps them responsive to demands of mature blood production. However, it is not known whether this process, termed lineage priming, directly influences HSC self-renewal. We investigated the link between stemness and lineage priming by attenuating the early lymphoid transcription factor E47 through ID2 over-expression (OE). Transcriptional profiling of ID2 OE HSCs showed down regulation of B-cell factors including EBF1 and FOXO1 with a concomitant increase in stemness programs and myeloerythroid factors including CEBPA and GATA1. This resulted in myeloid commitment bias from the earliest stages of differentiation. HSC self-renewal was strongly affected by this lineage perturbation resulting in an 11-fold expansion of HSCs. Thus, early lymphoid transcription factors antagonize human HSC self-renewal, providing a direct link between differentiation program priming and the maintenance of stem cell self-renewal.
2013-12-01 | GSE45486 | GEO
Project description:Combinatorial actions of relatively few transcription factors control hematopoietic differentiation. To investigate this process in erythro-megakaryopoiesis, we correlated the genome-wide chromatin occupancy signatures of four master hematopoietic transcription factors (GATA1, GATA2, TAL1, and FLI1) and three diagnostic histone modification marks with the gene expression changes that occur during development of primary cultured megakaryocytes (MEG) and primary erythroblasts (ERY) from murine fetal liver hematopoietic stem/progenitor cells. We identified a robust, genome-wide mechanism of MEG-specific lineage priming by a previously described stem/progenitor cell-expressed transcription factor heptad (GATA2, LYL1, TAL1, FLI1, ERG, RUNX1, LMO2) binding to MEG-associated cis-regulatory modules (CRMs) in multipotential progenitors. This is followed by genome-wide GATA factor switching that mediates further induction of MEG-specific genes following lineage commitment. Interaction between GATA and ETS factors appears to be a key determinant of these processes. In contrast, ERY-specific lineage priming is biased toward GATA2-independent mechanisms. In addition to its role in MEG lineage priming, GATA2 plays an extensive role in late megakaryopoiesis as a transcriptional repressor at loci defined by a specific DNA signature. Our findings reveal important new insights into how ERY and MEG lineages arise from a common bipotential progenitor via overlapping and divergent functions of shared hematopoietic transcription factors. Genome-wide chromatin occupancy using ChIP-seq on 4 transcription factors (GATA1, GATA2, TAL1, and FLII) and three histone marks (H3K4me1, H3K4me3, and H3K27me3) in lineage-commited primary erythoblasts (ERY) and primary cultured megakaryocytes (MEG).
2014-11-14 | E-GEOD-51337 | biostudies-arrayexpress
Project description:Studies of adult human hematopoiesis have until now relied on the expression of CD10 to define lymphoid commitment. We report a novel lymphoid-primed population in human bone marrow that is generated from hematopoietic stem cells (HSC) prior to the onset of CD10 expression and B cell commitment, and is identified by high levels of the homing molecule L-selectin (CD62L). CD10-CD62Lhi progenitors have full lymphoid (B/T/NK) potential, and show reduced myeloid and absent erythroid potential. Genome-wide gene expression analysis demonstrates that the CD10-CD62Lhi population represents an intermediate stage of differentiation between CD34+CD38- HSC and CD34+lin-CD10+ progenitors marked by down-regulation of TAL1 and MPL, upregulation of E2A, CD3E and IL2RG expression, and absent B cell commitment or RAG1/2 expression. Immature CD34+CD1a- thymocytes are also CD62Lhi and L-selectin ligands are expressed at the cortico-medullary junction, suggesting a possible role for L-selectin in human thymic homing. These studies identify the earliest stage of lymphoid priming in human bone marrow. Freshly harvested human bone marrow was ficoll purified, enriched for CD34+, and then FACS sorted. It was then sorted into 3 samples CD34+CD38-, CD34+ CD10- CD62L++, and CD34+ CD10+, with 3 independent biological replicates
2012-08-14 | E-GEOD-35685 | biostudies-arrayexpress
Project description:Combinatorial actions of relatively few transcription factors control hematopoietic differentiation. To investigate this process in erythro-megakaryopoiesis, we correlated the genome-wide chromatin occupancy signatures of four master hematopoietic transcription factors (GATA1, GATA2, SCL/TAL1 and FLI1) and three diagnostic histone modification marks with the gene expression changes that occur during development of primary megakaryocytes (MEG) and erythroblasts (ERY) from murine fetal liver hematopoietic stem/progenitor cells. We identified a robust, genome-wide mechanism of MEG-specific lineage priming by a previously described stem/progenitor cell-expressed transcription factor heptad (GATA2, LYL1, SCL/TAL1, FLI1, ERG, RUNX1, LMO2) binding to MEG-specific cis-regulatory modules in multipotential hematopoietic progenitors. This is followed by genome-wide GATA factor switching that mediates further induction of MEG-specific genes following lineage commitment. Interaction between GATA and ETS factors appears to be a key determinant of these processes. In contrast, ERY-specific lineage priming occurs is biased toward GATA2-independent mechanisms. In addition to its role in MEG lineage priming, GATA2 plays an extensive role in late megakaryopoiesis as a transcriptional repressor at loci defined by a specific DNA signature. Our findings reveal important new insights into how ERY and MEG lineages arise from a common bipotential precursor via overlapping and divergent functions of shared hematopoietic transcription factors. Gene expression changes during the development of primary megakaryocytes (MEG) and erythroblasts (ERY) from murine fetal liver hematopoietic stem/progenitor cells
2013-08-09 | E-GEOD-49664 | biostudies-arrayexpress