Durable Alterations of Hematopoiesis and Chromatin post-COVID-19 [snATAC-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE196989 | GEO | 2023/07/01
REPOSITORIES: GEO
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Project description:Acute SARS-CoV-2 infection is often highly inflammatory and protracted. Recent advances have established that inflammation can trigger innate immune memory and a persistent influence on hematopoietic development, through epigenetic mechanisms. However, these phenotypes and their molecular and cellular features are poorly described in humans. Here we reveal epigenomic alterations in innate immune and hematopoietic stem and progenitor cells (HSPC) post-COVID-19, with distinct molecular programs across disease severities. Enabled by novel approaches to study hematopoiesis from peripheral blood, we find persisting HSPC epigenetic programs conveyed, for months to a year, to short-lived progeny monocytes. These epigenetic changes are associated with increased myeloid cell differentiation and inflammatory and antiviral programs. We provide insights into post-infectious HSPC and innate immune cell epigenetic alterations that are broadly relevant.
2023-07-31 | GSE234939 | GEO
Project description:Acute SARS-CoV-2 infection is often highly inflammatory and protracted. Recent advances have established that inflammation can trigger innate immune memory and a persistent influence on hematopoietic development, through epigenetic mechanisms. However, these phenotypes and their molecular and cellular features are poorly described in humans. Here we reveal epigenomic alterations in innate immune and hematopoietic stem and progenitor cells (HSPC) post-COVID-19, with distinct molecular programs across disease severities. Enabled by novel approaches to study hematopoiesis from peripheral blood, we find persisting HSPC epigenetic programs conveyed, for months to a year, to short-lived progeny monocytes. These epigenetic changes are associated with increased myeloid cell differentiation and inflammatory and antiviral programs. We provide insights into post-infectious HSPC and innate immune cell epigenetic alterations that are broadly relevant.
2023-02-15 | GSE190004 | GEO
Project description:Acute SARS-CoV-2 infection is often highly inflammatory and protracted. Recent advances have established that inflammation can trigger innate immune memory and a persistent influence on hematopoietic development, through epigenetic mechanisms. However, these phenotypes and their molecular and cellular features are poorly described in humans. Here we reveal epigenomic alterations in innate immune and hematopoietic stem and progenitor cells (HSPC) post-COVID-19, with distinct molecular programs across disease severities. Enabled by novel approaches to study hematopoiesis from peripheral blood, we find persisting HSPC epigenetic programs conveyed, for months to a year, to short-lived progeny monocytes. These epigenetic changes are associated with increased myeloid cell differentiation and inflammatory and antiviral programs. We provide insights into post-infectious HSPC and innate immune cell epigenetic alterations that are broadly relevant.
2023-07-01 | GSE196988 | GEO
Project description:Acute SARS-CoV-2 infection is often highly inflammatory and protracted. Recent advances have established that inflammation can trigger innate immune memory and a persistent influence on hematopoietic development, through epigenetic mechanisms. However, these phenotypes and their molecular and cellular features are poorly described in humans. Here we reveal epigenomic alterations in innate immune and hematopoietic stem and progenitor cells (HSPC) post-COVID-19, with distinct molecular programs across disease severities. Enabled by novel approaches to study hematopoiesis from peripheral blood, we find persisting HSPC epigenetic programs conveyed, for months to a year, to short-lived progeny monocytes. These epigenetic changes are associated with increased myeloid cell differentiation and inflammatory and antiviral programs. We provide insights into post-infectious HSPC and innate immune cell epigenetic alterations that are broadly relevant.
2023-07-01 | GSE196987 | GEO
Project description:Here we describe that lysine-specific demethylase 1 (Lsd1/KDM1a), which demethylates histone H3 on LysM-bM-^@M-^I4 or LysM-bM-^@M-^I9 (H3K4/K9), is an indispensible epigenetic governor of hematopoietic differentiation. Integrative genomic analysis in primary hematopoietic cells, combining global occupancy of Lsd1, genome-wide analysis of its histone substrates H3K4 mono- and di-methylation and gene expression profiling, reveals that Lsd1 represses hematopoietic stem and progenitor cell (HSPC) gene expression programs during hematopoietic differentiation. We found that Lsd1 function was not restricted to transcription start sites, but is also critical at enhancers. Loss of Lsd1 at these sites was associated with increased H3K4me1 and H3K4me2 methylation levels on HSPC genes and their derepression. Failure to fully silence HSPC genes compromised differentiation of hematopoietic stem cells and mature blood cell lineages. Our data indicate that Lsd1-mediated concurrent repression of enhancer and promoter activity of stem and progenitor cell genes is a pivotal epigenetic mechanism required for proper hematopoietic maturation. To identify direct target genes of Lsd1 in myeloid cells we mapped global occupancy of Lsd1 in 32D granuolocytic progenitor cells and compared H3K4me1/me2/me3 and H3K27ac histone modifications in Lsd1fl/fl (wild type) vs. Lsd1fl/f Mx1Cre (knockout) Gr1dim Mac1 granuolocytic progenitor cells.
2013-06-25 | E-GEOD-40440 | biostudies-arrayexpress
Project description:TRAF-interacting protein with forkhead-associated domain B (TIFAB) is a haploinsufficient gene in del(5q) Myelodysplastic syndrome (MDS). Hematopoietic-specific deletion of Tifab results in progressive bone marrow (BM) and blood defects, including skewed hematopoietic stem/progenitor cells (HSPC) proportions, altered myeloid differentiation, and progressive cytopenia. A subset of mice transplanted with Tifab knockout (KO) hematopoietic cells develop a bone marrow failure (BMF)-like disease with neutrophil dysplasia and cytopenia. In competitive transplants, Tifab KO HSPC are out-competed by wild-type (WT) cells, suggesting a cell-intrinsic HSPC defect. Gene expression analysis of Tifab KO HSPC identified dysregulation of immune-related signatures, and hypersensitivity to Toll-like receptor 4 (TLR4) stimulation. TIFAB also forms a complex with TRAF6, a mediator of immune signaling, and reduces TRAF6 protein stability by a lysosome-dependent mechanism. In contrast, TIFAB loss increases TRAF6 protein and the dynamic range of TLR4 signaling in HSPC, contributing to ineffective hematopoiesis. Moreover, combined deletion of TIFAB and miR-146a, two genes associated with del(5q) MDS/AML, results in a cooperative increase in TRAF6 expression and hematopoietic dysfunction in vivo. Re-expression of TIFAB in human del(5q) leukemic cells results in attenuated TLR4 signaling and reduced cell viability. These findings underscore the importance of efficient regulation of innate immune/TRAF6 signaling within HSPC by TIFAB, and its cooperation with miR-146a as it relates to the pathogenesis of hematopoietic malignancies, such as del(5q) MDS/AML. We performed an expression analysis on sorted lineage-Sca1+cKit+ (LSK) isolated from bone marrow (BM) of 3 month old mice transplanted with Tifab+/+ (WT) or Tifab-/- (KO) BM cells (n = 3 mice/group). We selected this time point to capture the gene expression profile of Tifab-/- LSK after engraftment but prior to overt hematopoietic failure. Total RNA was extracted, purified, reverse transcribed, labeled, and hybridized onto the GeneChip MoGene 2.0 ST Array (Affymetrix). Comparison comprises mRNA expression profile of Tifab+/+ LSK vs. Tifab-/- LSK.
2015-09-12 | E-GEOD-72936 | biostudies-arrayexpress
Project description:Here we describe that lysine-specific demethylase 1 (Lsd1/KDM1a), which demethylates histone H3 on Lys 4 or Lys 9 (H3K4/K9), is an indispensible epigenetic governor of hematopoietic differentiation. Integrative genomic analysis in primary hematopoietic cells, combining global occupancy of Lsd1, genome-wide analysis of its histone substrates H3K4 mono- and di-methylation and gene expression profiling, reveals that Lsd1 represses hematopoietic stem and progenitor cell (HSPC) gene expression programs during hematopoietic differentiation. We found that Lsd1 function was not restricted to transcription start sites, but is also critical at enhancers. Loss of Lsd1 at these sites was associated with increased H3K4me1 and H3K4me2 methylation levels on HSPC genes and their derepression. Failure to fully silence HSPC genes compromised differentiation of hematopoietic stem cells and mature blood cell lineages. Our data indicate that Lsd1-mediated concurrent repression of enhancer and promoter activity of stem and progenitor cell genes is a pivotal epigenetic mechanism required for proper hematopoietic maturation.
2013-06-25 | GSE40440 | GEO
Project description:TRAF-interacting protein with forkhead-associated domain B (TIFAB) is a haploinsufficient gene in del(5q) Myelodysplastic syndrome (MDS). Hematopoietic-specific deletion of Tifab results in progressive bone marrow (BM) and blood defects, including skewed hematopoietic stem/progenitor cells (HSPC) proportions, altered myeloid differentiation, and progressive cytopenia. A subset of mice transplanted with Tifab knockout (KO) hematopoietic cells develop a bone marrow failure (BMF)-like disease with neutrophil dysplasia and cytopenia. In competitive transplants, Tifab KO HSPC are out-competed by wild-type (WT) cells, suggesting a cell-intrinsic HSPC defect. Gene expression analysis of Tifab KO HSPC identified dysregulation of immune-related signatures, and hypersensitivity to Toll-like receptor 4 (TLR4) stimulation. TIFAB also forms a complex with TRAF6, a mediator of immune signaling, and reduces TRAF6 protein stability by a lysosome-dependent mechanism. In contrast, TIFAB loss increases TRAF6 protein and the dynamic range of TLR4 signaling in HSPC, contributing to ineffective hematopoiesis. Moreover, combined deletion of TIFAB and miR-146a, two genes associated with del(5q) MDS/AML, results in a cooperative increase in TRAF6 expression and hematopoietic dysfunction in vivo. Re-expression of TIFAB in human del(5q) leukemic cells results in attenuated TLR4 signaling and reduced cell viability. These findings underscore the importance of efficient regulation of innate immune/TRAF6 signaling within HSPC by TIFAB, and its cooperation with miR-146a as it relates to the pathogenesis of hematopoietic malignancies, such as del(5q) MDS/AML.
2015-09-12 | GSE72936 | GEO
Project description:Upon systemic bacterial infection, hematopoietic stem and progenitor cells (HSPCs) migrate to the periphery in order to supply a sufficient number of immune cells. Although pathogen-associated molecular patterns (PAMPs) reportedly mediate HSPC activation, how HSPCs detect pathogen invasion in vivo remains elusive. Bacteria use the second messenger bis-(3’-5’)-cyclic dimeric guanosine monophosphate (c-di-GMP) for a variety of activities. Here we report that c-di-GMP comprehensively regulates both HSPCs and their niche cells through an innate immune sensor, STING, thereby inducing entry into the cell cycle and mobilization of HSPCs, while decreasing the number and repopulation capacity of long-term hematopoietic stem cells (LT-HSCs). Furthermore, we show that type I IFN acts as a downstream target of c-di-GMP to inhibit HSPC expansion in the spleen, while TGF-β1 is required for c-di-GMP-dependent splenic HSPC expansion. Our results define novel machinery underlying dynamic regulation of HSPCs and their niches during bacterial infection through c-di-GMP/STING signaling. Ten-week-old mice were intraperitoneally administered PBS or 200 nmol c-di-GMP, and CD150+ CD41- CD48- CD34- Flt3- LSK cells of pooled bone marrow from 10 mice per group were sorted 3 days later. mRNA was then extracted using RNeasy micro (Qiagen). Likewise, CD45- Ter-119- CD31- CD140a+ CD51+ MSCs and CD45- Ter119- CD31+ endothelial cells from c-di-GMP-treated or untreated mice were sorted and mRNA was extracted. cDNA was synthesized from mRNA and hybridized to gene chip Mouse60k (Agilent Technologies) and expression levels analyzed.
2015-02-13 | E-GEOD-65905 | biostudies-arrayexpress
Project description:Hematopoietic stem and progenitor cell (HSPC) formation and lineage differentiation involve gene expression programs orchestrated by transcription factors and epigenetic regulators. Knockdown of the chromatin remodeler chromodomain-helicase-DNA-binding protein 7 (CHD7) expanded phenotypic HSPCs, erythroid, and myeloid lineages in zebrafish and mouse embryos. CHD7 acts to suppress hematopoietic differentiation in a cell autonomous manner in the embryo and adult. We performed gene expression analysis to determine the expression of chd7 in adult sorted HSPC populations. Loss of Chd7 in long term hematopoietic stem cells (LT-HSCs) results in upregulation of genes that function in hematopoietic system development and function. Genes representative of each blood lineage including erythroid, myeloid, and lymphoid were upregulated, suggesting that Chd7 deficiency results in LT-HSCs that are more primed for multilineage differentiation. Together with the physical and genetic interaction, the data support a model in which CHD7 interacts with and modulates Runx1 activity to provide proper timing and function of HSPCs as they emerge during hematopoietic development or mature in adults. This represents a distinct and evolutionarily conserved control mechanism to ensure accurate hematopoietic lineage differentiation. We used microarrays to detail the expression of Chd7 in adult sorted HSPC populations.
2023-01-01 | GSE84127 | GEO