MutationPatterns_ASCs
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB12058 | ENA |
REPOSITORIES: ENA
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Project description:Mutations of embryonic and fetal origin have the potential to affect a large proportion of adult cells and may alter cancer predisposition or lead to genetic disease syndromes. We have recently shown that human adult-stem cells progressively acquire approximately 40 novel tissue-specific mutations per year throughout postnatal life. Prenatal mutation rates are as yet unknown. Here we determined genome-wide mutation patterns of single stem cells in human development by sequencing of clonally expanded intestinal and liver organoid cultures of 2nd trimester human foetuses. Our results show that mutation rates in fetal stem cells are significantly higher than in adult stem cells.
| EGAS00001002886 | EGA
Project description:Gradual accumulation of mutations in human adult stem cells during life is associated with various age-related diseases, including cancer. The number of stem cell divisions throughout life is believed to be a major determinant for mutation accumulation and could explain the extreme variation of cancer incidence across different organs. Yet, mutation patterns and rates of healthy adult stem cells remain unknown. Here, we determined genome-wide mutation patterns in primary adult stem cells of the small intestine, colon and liver of human donors with ages ranging from 3 to 87 years. We find that the number of mutations increases linearly with age up to several thousand mutations per cell at 87 years of age, while mutation spectra remain constant throughout life. Small intestine and colon stem cells have a 2-fold higher mutation rate per year compared with liver stem cells. These differences could be exclusively attributed to the mutagenic action of spontaneous deamination of cytosine residues and may reflect the high stem cell division rate in these tissues. The genomic distribution of somatic mutations is non-random and predominantly associated with DNA replication dynamics in the small intestine and colon, and with transcription in the liver. These results indicate that a stable balance between various mutagenic and DNA repair processes is maintained throughout life and that the activity of these processes in adult stem cells varies between tissues.
| EGAS00001001682 | EGA
Project description:Genetic changes acquired during culture pose a potential risk for the successful application of stem cells. To assess the risk of in vitro expansion on mutation accumulation we have performed whole genome sequencing of clonally expanded human induced pluripotent stem cells (iPS cells) and adult stem cells (ASCs) to identify all mutations that accumulated over a fixed culture period. We find that ASCs acquire more single nucleotide variants (SNVs) and indels per population doubling than the iPS cells. When compared with ASCs, iPS cells are more vulnerable to mutations in genes and promoters. Mutational analysis revealed a clear in vitro induced mutational signature that is irrespective of stem cell type. This in vitro signature is characterized by C to G transversions that are probably caused by oxidative stress. Additionally, we observed stem cell specific mutational signatures and differences in transcriptional strand bias, indicating differential activity of DNA repair mechanisms between stem cell types in culture. In conclusion, in vitro culture induces mutation accumulation in iPS cells and ASCs. Culture under low-oxygen tension may help to reduce the number of culture-induced mutations.
| EGAS00001002955 | EGA
Project description:Mutation accumulation during human life can contribute to hematopoietic dysfunction; however, the underlying dynamics are unknown. Somatic mutations in blood progenitors can provide insight into the rate and processes underlying this accumulation, as well as the developmental lineage tree and stem cell division numbers. Here, we catalogue somatic mutations in the genomes of human bone marrow-derived and cord blood-derived hematopoietic stem and multipotent progenitor cells (HSPCs) and find that base substitutions accumulate with approximately 17 base substitutions per year in both populations, while insertions and deletions occur sporadically and at low numbers. The majority of mutations in adult HSPCs were acquired after birth and could be explained by the constant activity of various endogenous processes, which also explains the mutation load in acute myeloid leukemia (AML). We construct a developmental lineage tree revealing a polyclonal architecture of the hematopoietic progenitor compartment and providing evidence that developmental clones exhibit multipotency, though lineage biases can be detected. Our approach highlights novel features of human native hematopoiesis and its implications for leukemogenesis.
| EGAS00001003068 | EGA
Project description:Whole genome sequencing data of organoid cultures derived from human bone marrow-derived and cord blood-derived hematopoietic stem and multipotent progenitor cells to study the mutation accumulation.
| EGAD00001004451 | EGA
Project description:Evidence indicates that the integrity of in utero embryonic development can influence late life healthy or unhealthy aging. However, specific links between embryonic development and late life aging are not well defined. Histone chaperone HIRA is thought to play a role in both early development and aging. Here, we explore the relationship between HIRA’s roles in development and aging by comparing lineage-specific constitutive and conditional Hira knock out in the murine pigmentary system, with constitutive knock out initiated during embryogenesis and conditional knock out in young adults. Embryonic Hira knockout leads to reduced melanoblast numbers during embryogenesis but wild type numbers of differentiated melanocytes at birth, normally functioning juvenile and young adult melanocyte stem cells (McSCs), and only a very mildly hypopigmented first hair coat. However, on closer analysis of these mice, Hira knockout melanocytic cells of newborn mice exhibit molecular markers characteristic of cell aging and proliferative deficits. As they age, mice with Hira knock out initiated during embryogenesis display marked defects in McSC maintenance and premature hair graying. Importantly, these defects are only observed when HIRA is inactivated during embryogenesis, but not in young adults. This genetic model shows that HIRA function during early development lays a foundation for subsequent maintenance of adult tissue specific stem cells during aging.
2025-06-11 | GSE267432 | GEO
Project description:Evidence indicates that the integrity of in utero embryonic development can influence late life healthy or unhealthy aging. However, specific links between embryonic development and late life aging are not well defined. Histone chaperone HIRA is thought to play a role in both early development and aging. Here, we explore the relationship between HIRA’s roles in development and aging by comparing lineage-specific constitutive and conditional Hira knock out in the murine pigmentary system, with constitutive knock out initiated during embryogenesis and conditional knock out in young adults. Embryonic Hira knockout leads to reduced melanoblast numbers during embryogenesis but wild type numbers of differentiated melanocytes at birth, normally functioning juvenile and young adult melanocyte stem cells (McSCs), and only a very mildly hypopigmented first hair coat. However, on closer analysis of these mice, Hira knockout melanocytic cells of newborn mice exhibit molecular markers characteristic of cell aging and proliferative deficits. As they age, mice with Hira knock out initiated during embryogenesis display marked defects in McSC maintenance and premature hair graying. Importantly, these defects are only observed when HIRA is inactivated during embryogenesis, but not in young adults. This genetic model shows that HIRA function during early development lays a foundation for subsequent maintenance of adult tissue specific stem cells during aging.
2025-06-11 | GSE267431 | GEO
Project description:Sox4 is a transcription factor expressed during embryonic development and some adult tissues such as lymphoid organs, pancreas, intestine and skin. During embryogenesis, Sox4 regulates the survival of mesenchymal and neural progenitors, lymphocyte and myeloid differentiation, and pancreatic, bone and cardiac development. Aberrantly increased Sox4 expression is linked to malignant transformation and metastasis in several types of human cancer. To study the role of Sox4 in the adult organism, we first generated mice with reduced whole-body Sox4 expression. These mice display a plethora of age-related degenerative disorders and reduced spontaneous cancer incidence, indicating a role for this protein in maintaining adult tissue homeostasis and in tumor growth. To specifically address a role for Sox4 in adult stem cells, we conditionally deleted Sox4 (Sox4cKO) in stratified epithelia. Sox4cKO mice show increased skin stem cell quiescence and DNA damage accumulation, accompanied by resistance to chemical carcinogenesis. These phenotypes correlate with downregulation of cell cycle, DNA repair and skin stem cell genes in the absence of Sox4. Altogether, these findings highlight the importance of Sox4 in adult tissue homeostasis and cancer. Sox4 WT and cKO (conditional KO in skin) were plucked and skin was collected for microarray hibridization, to study the contribution of Sox4 to hair regeneration and hair follicle stem cell activation
2015-05-20 | E-GEOD-58153 | biostudies-arrayexpress
Project description:Isocitrate dehydrogenase 1 mutations drive human gliomagenesis, probably through neomorphic enzyme activity that produces D-2-hydroxyglutarate. To model this disease, we conditionally expressed Idh1R132H in the subventricular zone (SVZ) of the adult mouse brain. The mice developed hydrocephalus and grossly dilated lateral ventricles, with accumulation of 2-hydroxyglutarate and reduced -ketoglutarate. Stem and transit amplifying/progenitor cell populations were expanded, and proliferation increased.Cells expressing SVZ markers infiltrated surrounding brain regions. SVZ cells also gave rise to proliferative subventricular nodules. DNA methylation was globally increased, while hydroxymethylation was decreased. Mutant SVZ cells over-expressed Wnt, cell cycle and stem cell genes, and shared an expression signature with human gliomas. Idh1R132H mutation in the major adult neurogenic stem cell niche causes a phenotype resembling gliomagenesis. Isocitrate dehydrogenase 1 mutations drive human gliomagenesis, probably through neomorphic enzyme activity that produces D-2-hydroxyglutarate. To model this disease, we conditionally expressed Idh1R132H in the subventricular zone (SVZ) of the adult mouse brain. The mice developed hydrocephalus and grossly dilated lateral ventricles, with accumulation of 2-hydroxyglutarate and reduced -ketoglutarate. Stem and transit amplifying/progenitor cell populations were expanded, and proliferation increased. Cells expressing SVZ markers infiltrated surrounding brain regions. SVZ cells also gave rise to proliferative subventricular nodules. DNA methylation was globally increased, while hydroxymethylation was decreased. Mutant SVZ cells over-expressed Wnt, cell cycle and stem cell genes, and shared an expression signature with human gliomas. Idh1R132H mutation in the major adult neurogenic stem cell niche causes a phenotype resembling gliomagenesis.
2017-01-30 | GSE85080 | GEO
Project description:Sox4 is a transcription factor expressed during embryonic development and some adult tissues such as lymphoid organs, pancreas, intestine and skin. During embryogenesis, Sox4 regulates the survival of mesenchymal and neural progenitors, lymphocyte and myeloid differentiation, and pancreatic, bone and cardiac development. Aberrantly increased Sox4 expression is linked to malignant transformation and metastasis in several types of human cancer. To study the role of Sox4 in the adult organism, we first generated mice with reduced whole-body Sox4 expression. These mice display a plethora of age-related degenerative disorders and reduced spontaneous cancer incidence, indicating a role for this protein in maintaining adult tissue homeostasis and in tumor growth. To specifically address a role for Sox4 in adult stem cells, we conditionally deleted Sox4 (Sox4cKO) in stratified epithelia. Sox4cKO mice show increased skin stem cell quiescence and DNA damage accumulation, accompanied by resistance to chemical carcinogenesis. These phenotypes correlate with downregulation of cell cycle, DNA repair and skin stem cell genes in the absence of Sox4. Altogether, these findings highlight the importance of Sox4 in adult tissue homeostasis and cancer. Sox4 WT and cKO (conditional KO in skin) skin was collected for microarray hybridization, to study the contribution of Sox4 to skin homeostasis in basal conditions (Telogen)
2015-05-20 | E-GEOD-58154 | biostudies-arrayexpress