Foxn1 choreographs both early and late events in thymic lympho-stromal cross-talk
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE75219 | GEO | 2016/08/09
SECONDARY ACCESSION(S): PRJNA302815
REPOSITORIES: GEO
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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:The transcription factor FOXN1 is a master regulator of thymic epithelial cell development and function. Here we demonstrate that FOXN1 expression is differentially regulated during organogenesis and participates in multi-molecular nuclear condensates essential for the factor's transcriptional activity. FOXN1's C-terminal sequence regulates the diffusion velocity within these aggregates and modulates the binding to proximal gene regulatory regions. These dynamics are significantly altered in a patient's FOXN1 mutant modified in its C-terminal sequence. This mutant is transcriptionally inactive and acts as a dominant negative factor displacing wild-type FOXN1 from condensates and causing athymia and severe lymphopenia in heterozygotes. Expression of the mutated mouse ortholog, Foxn1, selectively impairs mouse thymic epithelial cell (TEC) differentiation, revealing a gene dose dependency for individual TEC subtypes. We have therefore identified the cause for a primary immunodeficiency disease and determined the mechanism by which this FOXN1 gain-of-function mutant mediates its dominant negative effect.
2021-10-29 | PXD025552 | Pride
Project description:The transcription factor FOXN1 acts in a gene-dosage sensitive way as a master regulator of thymic epithelial cell development and maintenance enabling effective thymopoiesis. Its autosomal recessive loss of function is the molecular cause of the “nude” phenotype, a severe combined immunodeficiency caused by athymia. Here we report on a spontaneously occurring, novel heterozygous FOXN1 mutation that initially permits regular thymus organogenesis but results in a failure of thymic maintenance beyond late stages of human gestation. Modeling the mutation in mice results in divergent disruptions of normal TEC subtype differentiation and function. Transcriptionally inactive, the mutant disrupts the formation of wild type FOXN1 homo-multimers and occupies canonical DNA binding sites, at which it operates in a dominant negative fashion to displace wild type FOXN1 from nuclear condensates. Comparing the interactome of the mutant and wild type FOXN1 identified binding partners that uniquely interact with wild type FOXN1 and are characteristic constituents of nuclear organelles required for transcription. Mutant FOXN1 moves in and out of condensates over a time-course indistinguishable from that of wild type FOXN1, suggesting that the mutation did not affect the molecular movement of FOXN1. Thus, we have identified a clinically relevant gain of function mutation of FOXN1 that actively prevents the transcriptional activity of wild type FOXN1 and provides critical insight into the mechanism by which FOXN1 operates in controlling sustained gene expression necessary for normal thymic epithelial cell differentiation, maintenance and function.
2021-10-12 | GSE162668 | 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:FOXN1 is a transcription factor critical for the development of both thymic epithelial cell (TEC) and hair follicle cell (HFC) compartments. However, mechanisms controlling its expression remain poorly understood. To address this question, we performed thorough analyses of the conservation and chromatin status of the Foxn1 locus in different tissues and states, and identified several putative cis-regulatory regions unique to TEC vs. HFC. Furthermore, experiments using genetically modified mice with specific deletions in the Foxn1 locus and additional bioinformatic analyses helped us identify key regions and transcription factors involved in either positive or negative regulation of Foxn1 in both TEC and HFC. Specifically, we identified SIX1 and FOXN1 itself, as key factors inducing Foxn1 expression in embryonic and neonatal TECs. Together, our data provide important mechanistic insights into the transcriptional regulation of the Foxn1 gene in TEC vs. HFC and highlight the role of FOXN1 in its autoregulation
2022-08-03 | GSE192872 | GEO
Project description:FOXN1 is a transcription factor critical for the development of both thymic epithelial cell (TEC) and hair follicle cell (HFC) compartments. However, mechanisms controlling its expression remain poorly understood. To address this question, we performed thorough analyses of the conservation and chromatin status of the Foxn1 locus in different tissues and states, and identified several putative cis-regulatory regions unique to TEC vs. HFC. Furthermore, experiments using genetically modified mice with specific deletions in the Foxn1 locus and additional bioinformatic analyses helped us identify key regions and transcription factors involved in either positive or negative regulation of Foxn1 in both TEC and HFC. Specifically, we identified SIX1 and FOXN1 itself, as key factors inducing Foxn1 expression in embryonic and neonatal TECs. Together, our data provide important mechanistic insights into the transcriptional regulation of the Foxn1 gene in TEC vs. HFC and highlight the role of FOXN1 in its autoregulation
2022-08-03 | GSE192871 | GEO
Project description:FOXN1 is a transcription factor critical for the development of both thymic epithelial cell (TEC) and hair follicle cell (HFC) compartments. However, mechanisms controlling its expression remain poorly understood. To address this question, we performed thorough analyses of the conservation and chromatin status of the Foxn1 locus in different tissues and states, and identified several putative cis-regulatory regions unique to TEC vs. HFC. Furthermore, experiments using genetically modified mice with specific deletions in the Foxn1 locus and additional bioinformatic analyses helped us identify key regions and transcription factors involved in either positive or negative regulation of Foxn1 in both TEC and HFC. Specifically, we identified SIX1 and FOXN1 itself, as key factors inducing Foxn1 expression in embryonic and neonatal TECs. Together, our data provide important mechanistic insights into the transcriptional regulation of the Foxn1 gene in TEC vs. HFC and highlight the role of FOXN1 in its autoregulation
2022-08-03 | GSE198591 | GEO
Project description:FOXN1 is a transcription factor critical for the development of both thymic epithelial cell (TEC) and hair follicle cell (HFC) compartments. However, mechanisms controlling its expression remain poorly understood. To address this question, we performed thorough analyses of the conservation and chromatin status of the Foxn1 locus in different tissues and states, and identified several putative cis-regulatory regions unique to TEC vs. HFC. Furthermore, experiments using genetically modified mice with specific deletions in the Foxn1 locus and additional bioinformatic analyses helped us identify key regions and transcription factors involved in either positive or negative regulation of Foxn1 in both TEC and HFC. Specifically, we identified SIX1 and FOXN1 itself, as key factors inducing Foxn1 expression in embryonic and neonatal TECs. Together, our data provide important mechanistic insights into the transcriptional regulation of the Foxn1 gene in TEC vs. HFC and highlight the role of FOXN1 in its autoregulation
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Project description:FOXN1 is a transcription factor critical for the development of both thymic epithelial cell (TEC) and hair follicle cell (HFC) compartments. However, mechanisms controlling its expression remain poorly understood. To address this question, we performed thorough analyses of the conservation and chromatin status of the Foxn1 locus in different tissues and states, and identified several putative cis-regulatory regions unique to TEC vs. HFC. Furthermore, experiments using genetically modified mice with specific deletions in the Foxn1 locus and additional bioinformatic analyses helped us identify key regions and transcription factors involved in either positive or negative regulation of Foxn1 in both TEC and HFC. Specifically, we identified SIX1 and FOXN1 itself, as key factors inducing Foxn1 expression in embryonic and neonatal TECs. Together, our data provide important mechanistic insights into the transcriptional regulation of the Foxn1 gene in TEC vs. HFC and highlight the role of FOXN1 in its autoregulation
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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
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