The effect of E2F proteins on thymic hypo- and hyper-plasia
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE267456 | GEO | 2025/12/31
REPOSITORIES: GEO
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Project description:The effect of E2F proteins on thymic hypo- and hyper-plasia
| PRJNA1111540 | ENA
Project description:The thymus is a primary lymphoid organ that undergoes progressive age-associated involution, leading to reduced T cell output and impaired adaptive immunity. In this study, we employed scRNA-Seq as well as other approaches to reveal that medullary thymic epithelial cells (mTECs) produce excessive proinflammatory cytokines in the absence of Zfp36l1 and Zfp36l2, two RNA-binding proteins of TTP family. Consequently, FOXN1, a master regulator of pro-lymphopoietic genes in thymic epithelial cells, was down-regulated in young mice, which leads to premature thymic involution in knockout mice. These findings reveal a protective role for TTP family proteins in regulating cytokine levels within the thymic microenvironment and preventing premature thymic involution.
2026-01-09 | GSE315892 | GEO
Project description:The goal of this study was to document the gene expression profile of FOXN1+ thymic endoderm cells derived from the in vitro differentiation of human pluripotent stem cells. Thymic epithelial cells (TECs) play a critical role in T-cell maturation and tolerance induction. The generation of TECs from in vitro differentiation of human pluripotent stem cells (PSCs) would provide a platform for studying the mechanisms of this interaction and have implications for immune reconstitution. To facilitate analysis of PSC-derived TECs, we generated human embryonic stem cell (hESC) reporter lines in which sequences encoding GFP were targeted to FOXN1, a gene required for TEC development. Using this FOXN1GFP/w line as a read out, we developed a reproducible protocol for generating FOXN1-GFP+ thymic endoderm cells. Transcriptional profiling and flow cytometry identified Integrin-β4 (ITGB4, CD104) and HLA-DR as markers that could be used in combination with EpCAM to selectively purify FOXN1+ TEC progenitors from differentiating cultures of unmanipulated PSCs. Human FOXN1+ TEC progenitors generated from PSCs will facilitate the study of thymus biology and are a valuable resource for future applications in regenerative medicine Human embryonic stem cells were differentiated for 30 days using the protocol described by Soh et al, 2014. The hESCs used in this protocol had been genetically modified by targeting sequences encoding GFP to the FOXN1 locus, thus enabling FOXN1 expressing cells to be identified on the basis of GFP expression. At differentiation day 30, differentiating cells were separated into three fractions using FACS. These fractions were the FOXN1+(GFP+)EpCAM+, FOXN1-(GFP-)EpCAM+, FOXN1-(GFP-)EpCAM-.
2014-05-01 | E-GEOD-56373 | biostudies-arrayexpress
Project description:Normal thymic T cell development is enabled by a stromal microenvironment most importantly composed of distinct epithelial cell populations in cortex and medulla. Their differentiation, growth and function require the expression of the transcription factor Foxn1. Direct targets of Foxn1 have, however, remained largely undefined. Utilizing newly created static and inducible genetic model systems, we now provide a genome wide map of Foxn1 target genes and the sequences bound by this master regulator. Foxn1 controls not only essential steps early in intrathymic lymphoid development including T cell lineage commitment but is also indispensable for later stages in T cell maturation such as the selection of CD4 and CD8 T cells. Thus, Foxn1 function critically choreographs both early and late events in thymic lympho-stromal cross-talk. Foxn1 ChIP-seq and RNA-seq in mouse models of hypofunctional or conditional knock-out of Foxn1 Brief sample descriptions are shown below: Foxn1 ChIP-seq (GSM1945905) - chromatin immunoprecipitated using an antibody against FOXN1-FLAG (wt*); 2 samples Input ChIP-seq (GSM1945906) - input chromatin; 2 samples 42cT (GSM1945907) - RNA-seq on wt*/-::nu/nu cTEC; 3 samples 42mT (GSM1945908) - RNA-seq on wt*/-::nu/nu mTEC; 2 samples 96cT (GSM1945909) - RNA-seq on wt*/wt*::nu/nu cTEC; 3 samples 96mT (GSM1945910) - RNA-seq on wt*/wt*::nu/nu mTEC; 2 samples NcT (GSM1945911) - RNA-seq on Dox-treated TetO- iFoxn1(del7,8) cTEC; 5 samples PcT (GSM1945912) - RNA-seq on Dox-treated TetO+ iFoxn1(del7,8) cTEC; 5 samples C57BL/6 mice (GSM1945913) - ATAC-seq on wild-type cTEC; 1 sample Please see each sample for more detailed information.
2016-08-09 | E-GEOD-75219 | biostudies-arrayexpress
Project description:Normal thymic T cell development is enabled by a stromal microenvironment most importantly composed of distinct epithelial cell populations in cortex and medulla. Their differentiation, growth and function require the expression of the transcription factor Foxn1. Direct targets of Foxn1 have, however, remained largely undefined. Utilizing newly created static and inducible genetic model systems, we now provide a genome wide map of Foxn1 target genes and the sequences bound by this master regulator. Foxn1 controls not only essential steps early in intrathymic lymphoid development including T cell lineage commitment but is also indispensable for later stages in T cell maturation such as the selection of CD4 and CD8 T cells. Thus, Foxn1 function critically choreographs both early and late events in thymic lympho-stromal cross-talk.
2016-08-09 | GSE75219 | GEO
Project description:The generation of self-tolerant repertoires of T cells depends on the expression of peripheral self antigens in the thymic epithelium, and the presence of small populations of cells mimicking the diverse phenotypes of peripheral tissues. Whereas the molecular underpinnings of self-antigen expression have been extensively studied, the developmental origins and differentiation pathways of thymic mimetic cells remain to be identified. Moreover, the histological identification of myoid and other peripheral cell types as components of the thymic microenvironment of many vertebrate species raises questions as to the evolutionary origin of this unique tolerance mechanism. Here, we show that during mouse development, mimetic cells appear in the microenvironment in two successive waves. Cells exhibiting transcriptional signatures characteristic of muscle, ionocyte, goblet and ciliated cells emerge before birth, whereas others, for instance those mimicking enterohepatic cells and skin keratinocytes appear postnatally. These two groups also respond differently to modulations of TEC progenitor pools caused by deletions of Foxn1 and Ascl1, expression of a hypomorphic Foxn1 transcription factor, and overexpression of Bmp4 and Fgf7 signalling molecules. Differences in mimetic cell populations were also observed in thymic microenvironments reconstructed by replacement of mouse Foxn1 with evolutionarily ancient Foxn1/4 gene family members, including the Foxn4 gene of the cephalochordate amphioxus, and the Foxn4 and Foxn1 genes of a cartilaginous fish. Whereas some cell types, such as ciliated cells, develop in the thymus in the absence of Foxn1, mimetic cells appearing postnatally, such as enterohepatic cells, require the activity of the vertebrate-specific transcription factor Foxn1. The thymus of cartilaginous fishes and the thymoid of lampreys, a representative of jawless vertebrates that exhibit an alternative adaptive immune system, also harbour cells expressing genes encoding peripheral tissue components, such as the liver-specific protein transthyretin. Our findings suggest an evolutionary model of successive changes of thymic epithelial genetic networks enabling the coordinated contribution of peripheral antigen expression and mimetic cell formation to achieve central tolerance for vertebrate-specific innovations of certain tissues, such as the liver.
2025-04-15 | GSE272144 | GEO
Project description:The generation of self-tolerant repertoires of T cells depends on the expression of peripheral self antigens in the thymic epithelium, and the presence of small populations of cells mimicking the diverse phenotypes of peripheral tissues. Whereas the molecular underpinnings of self-antigen expression have been extensively studied, the developmental origins and differentiation pathways of thymic mimetic cells remain to be identified. Moreover, the histological identification of myoid and other peripheral cell types as components of the thymic microenvironment of many vertebrate species raises questions as to the evolutionary origin of this unique tolerance mechanism. Here, we show that during mouse development, mimetic cells appear in the microenvironment in two successive waves. Cells exhibiting transcriptional signatures characteristic of muscle, ionocyte, goblet and ciliated cells emerge before birth, whereas others, for instance those mimicking enterohepatic cells and skin keratinocytes appear postnatally. These two groups also respond differently to modulations of TEC progenitor pools caused by deletions of Foxn1 and Ascl1, expression of a hypomorphic Foxn1 transcription factor, and overexpression of Bmp4 and Fgf7 signalling molecules. Differences in mimetic cell populations were also observed in thymic microenvironments reconstructed by replacement of mouse Foxn1 with evolutionarily ancient Foxn1/4 gene family members, including the Foxn4 gene of the cephalochordate amphioxus, and the Foxn4 and Foxn1 genes of a cartilaginous fish. Whereas some cell types, such as ciliated cells, develop in the thymus in the absence of Foxn1, mimetic cells appearing postnatally, such as enterohepatic cells, require the activity of the vertebrate-specific transcription factor Foxn1. The thymus of cartilaginous fishes and the thymoid of lampreys, a representative of jawless vertebrates that exhibit an alternative adaptive immune system, also harbour cells expressing genes encoding peripheral tissue components, such as the liver-specific protein transthyretin. Our findings suggest an evolutionary model of successive changes of thymic epithelial genetic networks enabling the coordinated contribution of peripheral antigen expression and mimetic cell formation to achieve central tolerance for vertebrate-specific innovations of certain tissues, such as the liver.
2025-04-15 | GSE272064 | GEO
Project description:The generation of self-tolerant repertoires of T cells depends on the expression of peripheral self antigens in the thymic epithelium, and the presence of small populations of cells mimicking the diverse phenotypes of peripheral tissues. Whereas the molecular underpinnings of self-antigen expression have been extensively studied, the developmental origins and differentiation pathways of thymic mimetic cells remain to be identified. Moreover, the histological identification of myoid and other peripheral cell types as components of the thymic microenvironment of many vertebrate species raises questions as to the evolutionary origin of this unique tolerance mechanism. Here, we show that during mouse development, mimetic cells appear in the microenvironment in two successive waves. Cells exhibiting transcriptional signatures characteristic of muscle, ionocyte, goblet and ciliated cells emerge before birth, whereas others, for instance those mimicking enterohepatic cells and skin keratinocytes appear postnatally. These two groups also respond differently to modulations of TEC progenitor pools caused by deletions of Foxn1 and Ascl1, expression of a hypomorphic Foxn1 transcription factor, and overexpression of Bmp4 and Fgf7 signalling molecules. Differences in mimetic cell populations were also observed in thymic microenvironments reconstructed by replacement of mouse Foxn1 with evolutionarily ancient Foxn1/4 gene family members, including the Foxn4 gene of the cephalochordate amphioxus, and the Foxn4 and Foxn1 genes of a cartilaginous fish. Whereas some cell types, such as ciliated cells, develop in the thymus in the absence of Foxn1, mimetic cells appearing postnatally, such as enterohepatic cells, require the activity of the vertebrate-specific transcription factor Foxn1. The thymus of cartilaginous fishes and the thymoid of lampreys, a representative of jawless vertebrates that exhibit an alternative adaptive immune system, also harbour cells expressing genes encoding peripheral tissue components, such as the liver-specific protein transthyretin. Our findings suggest an evolutionary model of successive changes of thymic epithelial genetic networks enabling the coordinated contribution of peripheral antigen expression and mimetic cell formation to achieve central tolerance for vertebrate-specific innovations of certain tissues, such as the liver.
2025-04-15 | GSE288957 | GEO
Project description:The generation of self-tolerant repertoires of T cells depends on the expression of peripheral self antigens in the thymic epithelium, and the presence of small populations of cells mimicking the diverse phenotypes of peripheral tissues. Whereas the molecular underpinnings of self-antigen expression have been extensively studied, the developmental origins and differentiation pathways of thymic mimetic cells remain to be identified. Moreover, the histological identification of myoid and other peripheral cell types as components of the thymic microenvironment of many vertebrate species raises questions as to the evolutionary origin of this unique tolerance mechanism. Here, we show that during mouse development, mimetic cells appear in the microenvironment in two successive waves. Cells exhibiting transcriptional signatures characteristic of muscle, ionocyte, goblet and ciliated cells emerge before birth, whereas others, for instance those mimicking enterohepatic cells and skin keratinocytes appear postnatally. These two groups also respond differently to modulations of TEC progenitor pools caused by deletions of Foxn1 and Ascl1, expression of a hypomorphic Foxn1 transcription factor, and overexpression of Bmp4 and Fgf7 signalling molecules. Differences in mimetic cell populations were also observed in thymic microenvironments reconstructed by replacement of mouse Foxn1 with evolutionarily ancient Foxn1/4 gene family members, including the Foxn4 gene of the cephalochordate amphioxus, and the Foxn4 and Foxn1 genes of a cartilaginous fish. Whereas some cell types, such as ciliated cells, develop in the thymus in the absence of Foxn1, mimetic cells appearing postnatally, such as enterohepatic cells, require the activity of the vertebrate-specific transcription factor Foxn1. The thymus of cartilaginous fishes and the thymoid of lampreys, a representative of jawless vertebrates that exhibit an alternative adaptive immune system, also harbour cells expressing genes encoding peripheral tissue components, such as the liver-specific protein transthyretin. Our findings suggest an evolutionary model of successive changes of thymic epithelial genetic networks enabling the coordinated contribution of peripheral antigen expression and mimetic cell formation to achieve central tolerance for vertebrate-specific innovations of certain tissues, such as the liver.
2025-04-15 | GSE272063 | GEO
Project description:The goal of this study was to document the gene expression profile of FOXN1+ thymic endoderm cells derived from the in vitro differentiation of human pluripotent stem cells. Thymic epithelial cells (TECs) play a critical role in T-cell maturation and tolerance induction. The generation of TECs from in vitro differentiation of human pluripotent stem cells (PSCs) would provide a platform for studying the mechanisms of this interaction and have implications for immune reconstitution. To facilitate analysis of PSC-derived TECs, we generated human embryonic stem cell (hESC) reporter lines in which sequences encoding GFP were targeted to FOXN1, a gene required for TEC development. Using this FOXN1GFP/w line as a read out, we developed a reproducible protocol for generating FOXN1-GFP+ thymic endoderm cells. Transcriptional profiling and flow cytometry identified Integrin-β4 (ITGB4, CD104) and HLA-DR as markers that could be used in combination with EpCAM to selectively purify FOXN1+ TEC progenitors from differentiating cultures of unmanipulated PSCs. Human FOXN1+ TEC progenitors generated from PSCs will facilitate the study of thymus biology and are a valuable resource for future applications in regenerative medicine
2014-05-01 | GSE56373 | GEO