Thymic epithelia amplify noise in chromatin accessibility via p53 repression to impose immune tolerance
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ABSTRACT:
PROVIDER: PRJNA1145966 | ENA |
REPOSITORIES: ENA
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Project description:Thymic epithelia amplify noise in chromatin accessibility via p53 repression to impose immune tolerance [RNA-seq]
| PRJNA1145955 | ENA
Project description:Thymic epithelia amplify noise in chromatin accessibility via p53 repression to impose immune tolerance [CUT&Run]
| PRJNA1229619 | ENA
Project description:Thymic epithelia amplify noise in chromatin accessibility via p53 repression to impose immune tolerance [P53-WT-cKO_BulkRNA]
| PRJNA1287484 | ENA
Project description:Phenotypic plasticity of somatic cells is a principal feature of vertebrate adaptation as well as a hallmark of tumorigenesis. However, the determinants and mechanisms that regulate the stability of somatic cell identities remain unclear. Here, using the somatic plasticity of thymic epithelial cells – which facilitates the selection of a self-discriminating T cell repertoire – as a physiological model system, we show that stochastic fluctuations in background chromatin accessibility at nucleosome-dense regions are amplified by thymic epithelial cells to ectopically express thousands of genes highly restricted to other specialized cell types. We found broad regions of inaccessible chromatin flanking tissue-specific genes become ‘destabilized’ during thymic epithelial maturation independently of AIRE-induced transcription of these genes, but concurrently with the repression of the tumor suppressor p53. Augmenting p53 activity in thymic epithelial cells reduced noise in chromatin accessibility at nucleosome-dense regions, inhibited ectopic expression of tissue-specific genes and caused multi-organ autoimmunity. Furthermore, we found p53-regulated fluctuations in background chromatin accessibility in lung adenocarcinoma to be associated with high plasticity states that promote tumor progression. Taken together, our findings establish p53-dependent stabilization of nucleosomal barriers to cellular reprogramming as a fulcrum of cell fate integrity that underlies critical components of immune tolerance induction and oncogenic potential.
2025-06-30 | GSE274324 | GEO
Project description:Phenotypic plasticity of somatic cells is a principal feature of vertebrate adaptation as well as a hallmark of tumorigenesis. However, the determinants and mechanisms that regulate the stability of somatic cell identities remain unclear. Here, using the somatic plasticity of thymic epithelial cells – which facilitates the selection of a self-discriminating T cell repertoire – as a physiological model system, we show that stochastic fluctuations in background chromatin accessibility at nucleosome-dense regions are amplified by thymic epithelial cells to ectopically express thousands of genes highly restricted to other specialized cell types. We found broad regions of inaccessible chromatin flanking tissue-specific genes become ‘destabilized’ during thymic epithelial maturation independently of AIRE-induced transcription of these genes, but concurrently with the repression of the tumor suppressor p53. Augmenting p53 activity in thymic epithelial cells reduced noise in chromatin accessibility at nucleosome-dense regions, inhibited ectopic expression of tissue-specific genes and caused multi-organ autoimmunity. Furthermore, we found p53-regulated fluctuations in background chromatin accessibility in lung adenocarcinoma to be associated with high plasticity states that promote tumor progression. Taken together, our findings establish p53-dependent stabilization of nucleosomal barriers to cellular reprogramming as a fulcrum of cell fate integrity that underlies critical components of immune tolerance induction and oncogenic potential.
2025-06-30 | GSE290716 | GEO
Project description:Phenotypic plasticity of somatic cells is a principal feature of vertebrate adaptation as well as a hallmark of tumorigenesis. However, the determinants and mechanisms that regulate the stability of somatic cell identities remain unclear. Here, using the somatic plasticity of thymic epithelial cells – which facilitates the selection of a self-discriminating T cell repertoire – as a physiological model system, we show that stochastic fluctuations in background chromatin accessibility at nucleosome-dense regions are amplified by thymic epithelial cells to ectopically express thousands of genes highly restricted to other specialized cell types. We found broad regions of inaccessible chromatin flanking tissue-specific genes become ‘destabilized’ during thymic epithelial maturation independently of AIRE-induced transcription of these genes, but concurrently with the repression of the tumor suppressor p53. Augmenting p53 activity in thymic epithelial cells reduced noise in chromatin accessibility at nucleosome-dense regions, inhibited ectopic expression of tissue-specific genes and caused multi-organ autoimmunity. Furthermore, we found p53-regulated fluctuations in background chromatin accessibility in lung adenocarcinoma to be associated with high plasticity states that promote tumor progression. Taken together, our findings establish p53-dependent stabilization of nucleosomal barriers to cellular reprogramming as a fulcrum of cell fate integrity that underlies critical components of immune tolerance induction and oncogenic potential.
2025-06-30 | GSE274320 | GEO
Project description:Phenotypic plasticity of somatic cells is a principal feature of vertebrate adaptation as well as a hallmark of tumorigenesis. However, the determinants and mechanisms that regulate the stability of somatic cell identities remain unclear. Here, using the somatic plasticity of thymic epithelial cells – which facilitates the selection of a self-discriminating T cell repertoire – as a physiological model system, we show that stochastic fluctuations in background chromatin accessibility at nucleosome-dense regions are amplified by thymic epithelial cells to ectopically express thousands of genes highly restricted to other specialized cell types. We found broad regions of inaccessible chromatin flanking tissue-specific genes become ‘destabilized’ during thymic epithelial maturation independently of AIRE-induced transcription of these genes, but concurrently with the repression of the tumor suppressor p53. Augmenting p53 activity in thymic epithelial cells reduced noise in chromatin accessibility at nucleosome-dense regions, inhibited ectopic expression of tissue-specific genes and caused multi-organ autoimmunity. Furthermore, we found p53-regulated fluctuations in background chromatin accessibility in lung adenocarcinoma to be associated with high plasticity states that promote tumor progression. Taken together, our findings establish p53-dependent stabilization of nucleosomal barriers to cellular reprogramming as a fulcrum of cell fate integrity that underlies critical components of immune tolerance induction and oncogenic potential.
2025-07-08 | GSE301724 | GEO
Project description:Thymic epithelial cells (TECs) are essential for thymopoiesis and form a complex three-dimensional network, the organization of which is strikingly different from other epithelia. Interestingly, TECs express simple epithelia keratins in the cortex, stratified epithelia keratins in the medulla and epidermal differentiation markers in Hassall's bodies. Here we investigate the relationship between thymic epithelium and epidermal differentiation and show that the thymus of the rat contains a population of clonogenic TECs that can be extensively cultured and cloned using conditions developed for epidermal cell therapy in human. Clonogenic TECs conserve a thymic identity and the capacity to integrate in a thymic epithelial network, but they acquire new functionalities when exposed to an inductive skin microenvironment, permanently adopting the fate of hair follicle multipotent stem cells. This change in fate, maintained over time in serial transplantation, correlates with a down-regulation of transcription factors important for thymic identity, and an up-regulation of epidermal markers. Consequently, the TECs’ capacity to integrate in a thymic epithelial network is altered or even lost. Our results demonstrate that the thymus contains a population of holoclone-like epithelial cells that can function as bona fide multipotent keratinocyte stem cells, and that microenvironmental cues are sufficient to re-direct epithelial-cell fate, allowing crossing of primitive germ layer boundaries from endoderm to ectoderm. Keywords: Cell type comparison
2010-08-23 | GSE21686 | GEO
Project description:Stochastic fluctuations (noise) in transcription generate substantial cell-to-cell variability, but the physiological roles of noise have remained difficult to determine in the absence of generalized noise-modulation approaches. Previous single-cell RNA-sequencing (scRNA-seq) suggested that the pyrimidine-base analog (5′-iodo-2′-deoxyuridine, IdU) could generally amplify noise without substantially altering mean-expression levels but scRNA-seq technical drawbacks potentially obscured the penetrance of IdU-induced transcriptional noise amplification. Here we quantify global-vs.-partial penetrance of IdU-induced noise amplification by assessing scRNA-seq data using numerous normalization algorithms and complement our previous results with data from Human Jurkat T Lymphocytes, including two biological replicates to allow rigorous statistical analysis. Collectively, this analysis indicates which scRNA-seq algorithms are appropriate for quantifying noise and argues that IdU is a globally penetrant noise-enhancer molecule that could enable investigations of the physiological impacts of transcriptional noise in various cell types and organisms.
2024-08-28 | GSE263194 | GEO
Project description:Fuzziness and noise in nucleosomal architecture
| PRJEB4709 | ENA