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ABSTRACT:
PROVIDER: PRJNA1055136 | ENA |
REPOSITORIES: ENA
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Project description:Aging-associated microbial metabolite influences clonal hematopoiesis via ALPK1 [RNA-seq]
| PRJNA973978 | ENA
Project description:Despite the known associations between CHIP and increased all-cause mortality, our understanding of environmental and regulatory factors that underlie this process during aging remain rudimentary. Here we report that intestinal alterations, which can occur with age, lead to systemic dissemination of a microbial metabolite that promotes leukemic cell expansion. Specifically, we show that ADP-D-glycero-b-D-manno-heptose (ADP-heptose), a biosynthetic bi-product specific to gram-negative bacteria, is uniquely found in the circulation of older individuals and favors the expansion of pre-leukemic hematopoietic stem cells. Mechanistically, ADP-heptose binds its receptor, ALPK1, triggering transcriptional reprogramming that endows pre-leukemic cells with a competitive advantage. Thus, the accumulation of ADP-heptose represents a direct link between aging and expansion of rare pre-leukemic cells, suggesting that the ADP-heptose-ALPK1 axis is a promising therapeutic target to prevent progression of CHIP to overt leukemia and immune-related conditions.
2025-02-10 | GSE232794 | GEO
Project description:Somatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH). However, how ASXL1 mutations drive CH remains elusive. Using knockin (KI) mice expressing a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), we examined the influence of ASXL1-MT on physiological aging in hematopoietic stem cells (HSCs). HSCs expressing ASXL1-MT display competitive disadvantage after transplantation. Nevertheless, in genetic mosaic mouse model, they acquire clonal advantage during aging, recapitulating CH in humans. Mechanistically, ASXL1-MT cooperates with BAP1 to deubiquitinate and activate AKT. Overactive Akt/mTOR signaling induced by ASXL1-MT results in aberrant proliferation and dysfunction of HSCs associated with age-related accumulation of DNA damage. Treatment with an mTOR inhibitor rapamycin ameliorates aberrant expansion of the HSC compartment as well as dysregulated hematopoiesis in aged ASXL1-MT KI mice. Our findings suggest that ASXL1-MT provokes dysfunction of HSCs, whereas it confers clonal advantage on HSCs over time, leading to the development of CH.
2021-02-08 | MSV000086816 | MassIVE
Project description:Clonal hematopoiesis of aging results from enhanced fitness of mutant hematopoietic stem cells (HSCs) and associates with both favorable and unfavorable health outcomes related to lineage cell types produced by mutant HSCs. The extent to which lineage output can be controlled in clonal hematopoiesis is unknown. Using a mouse model of DNMT3AR882/+ clonal hematopoiesis (Dnmt3aR878H/+), we find that aging-induced TNFα signaling drives selective advantage of mutant HSCs concomitant with B lymphoid lineage production. Genetic loss of TNFα receptor TNFR1 impaired mutant HSC fitness while loss of TNFR2 abrogated lymphoid production and resulted in unrestrained myeloid cell production from mutant HSCs. These results support a model where clone size and lineage output can be independently targeted to harness potential beneficial aspects of clonal hematopoiesis.
2021-11-25 | GSE189406 | GEO
Project description:The bacterial metabolite ADP-heptose activates the mammalian protein kinase ALPK1 (alpha protein kinase 1), which then phosphorylates TIFA (TRAF interacting protein with FHA domain). This leads to the oligomerisation of TIFA and the recruitment and oligomerisation of TRAF6 (TNF receptor-associated factor 6), activating a signalling network that culminates in the production of inflammatory mediators that mount responses to combat microbial infection. To identify other protein(s) that associate with TRAF6 in ADP-heptose-stimulated cells, we re-expressed FLAG-TRAF6 in TRAF6 KO cells, stimulated the cells with ADP-heptose and immunoprecipitated TRAF6 from the cell extracts using a FLAG antibody. Proteins associated with TRAF6 were identified by mass spectrometry and included the components of LUBAC (the linear ubiquitin assembly complex), the components of the TAK1 and IB kinase (IKK) complexes, TRAF2 and c-IAP1, providing insight into the molecular details and mode of operation of the ADP-heptose signalling pathway. In parallel experiments the cells were stimulated with IL-1b, a cytokine that also signals via TRAF6, which served as a control.
2022-09-14 | PXD034964 | Pride
Project description:Hematopoietic stem cell (HSC) aging is accompanied by hematopoietic reconstitution dysfunction, including loss of regenerative and engraftment ability, myeloid differentiation bias and elevated risks of hematopoietic malignancies. Gut microbiota, a key regulator of host health and immunity, has been recently reported to impact hematopoiesis. However, there is currently no empirical evidence elucidating the direct impact of gut microbiome on aging hematopoiesis. To assess these potential effects, we performed fecal microbiota transplantation (FMT) from young mice to aged mice and observed an increment in both the absolute number and the engraftment ability of HSCs. Single cell RNA sequencing depicted overall transcriptional changes of HSCs as well as the bone marrow microenvironment and indicated that gut microbiota from young mice enhanced cell cycle activity of HSCs, attenuated canonical inflammatory signals and mitigated inflammation-associated phenotypes in aging hematopoiesis. Integrated microbiome-metabolome analysis uncovered that FMT reshaped gut microbiota construction and metabolite landscape, while the administration of Lachnospiraceae and tryptophan-associated metabolites promoted the recovery of hematopoiesis and rejuvenated aged HSCs. Together, our results highlighted the paramount importance of the gut microbiota in HSC aging and provided a strong rationale to limit hematopoietic exhaustion and treat hematologic disorders.
2023-08-15 | GSE201920 | GEO
Project description:<p>Hematopoietic stem cell (HSC) mutations can result in clonal hematopoiesis (CH) with heterogeneous clinical outcomes. Here, we investigated how the cell state preceding <em>Tet2</em> mutation impacts the pre-malignant phenotype. Using an inducible system for clonal analysis of myeloid progenitors, we found that the epigenetic features of clones at similar differentiation status were highly heterogeneous and functionally responded differently to <em>Tet2</em> mutation. Cell differentiation stage also influenced <em>Tet2</em> mutation response indicating that the cell of origin's epigenome modulates clone-specific behaviors in CH. Molecular features associated with higher risk outcomes include <em>Sox4</em> that sensitized cells to <em>Tet2</em> inactivation, inducing dedifferentiation, altered metabolism and increasing the <em>in vivo</em> clonal output of mutant cells, as confirmed in primary GMP and HSC models. Our findings validate the hypothesis that epigenetic features can predispose specific clones for dominance, explaining why identical genetic mutations can result in different phenotypes.</p>
1970-01-01 | MTBLS9914 | MetaboLights
Project description:Microbial dysbiosis is a colorectal cancer (CRC) hallmark and contributes to inflammation, tumor growth, and therapy response. Gut microbes signal via metabolites, but how the metabolites impact CRC is largely unknown. We interrogated fecal metabolites associated with mouse models of colon tumorigenesis with varying mutational load. We found that microbial metabolites from healthy mice or humans were growth-repressive, and this response was attenuated in mice and patients with CRC. Microbial profiling revealed that Lactobacillus reuteri and its metabolite, reuterin were downregulated in mouse and human CRC. Reuterin altered redox balance, and reduced survival, and proliferation in colon cancer cells. Reuterin induced selective protein oxidation, and inhibited ribosomal biogenesis and protein translation. Exogenous Lactobacillus reuteri restricted mouse colon tumor growth, increased tumor reactive oxygen species, and decreased protein translation in vivo. Our findings indicate that a healthy microbiome and specifically, Lactobacillus reuteri, is protective against CRC through microbial metabolite exchange.
2021-12-12 | GSE186880 | GEO
Project description:Clonal hematopoiesis resulting from enhanced fitness of mutant hematopoietic stem cells (HSCs) associates with both favorable and unfavorable health outcomes related to the types of mature mutant blood cells produced, but how this lineage output is regulated is unclear. Using a mouse model of DNMT3AR882/+ clonal hematopoiesis (Dnmt3aR878H/+), we found that aging-induced TNFα signaling promoted the selective advantage of mutant HSCs as well as stimulated mutant B lymphoid cell production. Genetic loss of TNFα receptor TNFR1 impaired mutant HSC fitness without altering lineage output, while loss of TNFR2 reduced lymphoid cell production and favored myeloid cell production from mutant HSCs without altering overall fitness. These results support a model where clone size and mature blood lineage production can be independently controlled to harness potential beneficial aspects of clonal hematopoiesis.
2022-05-25 | GSE203550 | GEO
Project description:Clonal hematopoiesis is associated with protection from Alzheimer's disease
| PRJNA793670 | ENA