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RNA-seq profiling of epithelial cells from fetal thymic organ cultures from Kat7 knockout and wildtype mice

ABSTRACT: RNA-seq profiling of epithelial cells from fetal thymic organ cultures from Kat7 knockout and wildtype mice

PROVIDER: PRJNA780540 | ENA |

REPOSITORIES: ENA

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RNA-seq profiling of epithelial cells from fetal thymic organ cultures from Kat7 knockout and wildtype mice

Project description:Thymic epithelial cells (TECs) govern thymic T lymphocyte differentiation and selection. Medullary TECs are distinctive for their "promiscuous" gene expression, transcribing thousands of peripheral tissue genes (PTG) that are otherwise only expressed highly in one or two other organs. Much of this PTG expression by mTECs is controlled by the autoimmune regulator, AIRE. This experiment was part of a larger study in which we examined the impact of Kat7 loss on AIRE-mediated PTG expression. Despite the apparently normal differentiation of AIRE+ TECs in Kat7-knockout mice, it was possible that the defect in AIRE-mediated PTG expression was secondary to the developmental loss of this histone acetyltransferase. To address this hypothesis, we employed fetal thymic organ cultures (FTOC) depleted of thymocytes where AIRE+ mTEC and PTG expression was induced by an agonist anti-RANK antibody. We then used two different approaches to acutely block KAT7 function and subsequently sort purified TECs for RNA-seq analysis to assess the impact on AIRE-mediated PTG transcription. AIRE+ mTECs exhibit relatively low turnover in organ culture; therefore, this approach uncouples KAT7 impacts on AIRE function from potential influences on TEC differentiation. Our first approach employed a new small molecule inhibitor of KAT7 function, WM-3835. The second approach was an inducible genetic deletion system. FTOC established with thymi from control (Kat7fl/fl) or RosaCre-ERT2 Kat7fl/fl mice were treated with tamoxifen to activate CRE-mediated deletion of Kat7.

2021-12-21 | GSE188869 | GEO

ATAC-seq profiling of medullary thymic epithelial cells from wildtype and Kat7-knockout mice

Project description:Thymic epithelial cells govern thymic T lymphocyte differentiation and selection. Medullary TECs (mTECs) facilitate the negative selection of self-reactive thymocytes and the differentiation of FOXP3+ regulatory T cells. Medullary TECs are also distinctive for their “promiscuous” gene expression, transcribing thousands of peripheral tissue genes (PTG) that are otherwise only expressed highly in one or two other organs. Much of this PTG expression by mTECs is controlled by the autoimmune regulator, AIRE. To probe the mechanism by which KAT7 promotes AIRE function, we performed ATAC-seq to compare chromatin accessibility in MHCII-high medullary thymic epithelial cells from Kat7-knockout and wildtype mice.

2021-12-21 | GSE188868 | GEO

RNA-seq and ATAC-seq profiling of thymic epithelial cells from wildtype and Kat7 knockout mice

Project description:The autoimmune regulator, AIRE, induces the transcription of thousands of peripheral tissue genes (PTGs) in thymic epithelial cells (TECs) to mediate immunological tolerance. The chromatin state required for optimal AIRE function in TECs and how this state is induced remains unclear. Using RNA-seq and ATAC-seq, we tested the role of the histone acetyltransferase, KAT7 (also known as HBO1 or MYST2), which is essential for acetylation of histone 3 lysine 14 (H3K14), in TEC differentiation, AIRE-mediated PTG expression and thymic tolerance. We find that KAT7 is required for optimal expansion of medullary TEC and has a major role in the expression of AIRE-dependent PTGs, associated with enhanced chromatin accessibility at these gene loci in TECs. Mice with TEC-specific Kat7 deletion develop organ-specific autoimmunity with features resembling those observed in Aire-deficient mice. These findings highlight critical roles for KAT7-mediated acetylation in promoting a chromatin state at PTG loci that enables AIRE function and the establishment of immunological tolerance.

2021-12-21 | GSE188871 | GEO

RNA-seq profiling of cortical and medullary thymic epithelial cells from wildtype and Kat7 knockout mice

Project description:Thymic epithelial cells (TECs) govern thymic T lymphocyte differentiation and selection. They can be divided into cortical and medullary TECs based on their anatomical location, function and molecular features. Cortical TECs (cTECs) provide the microenvironment for the commitment of haematopoietic precursors to the T lymphoid lineage and mediate the positive selection of CD4+CD8+ double-positive thymocytes. Medullary TECs (mTECs) facilitate the negative selection of self-reactive thymocytes and the differentiation of FOXP3+ regulatory T (Treg) cells2. Medullary TECs are also distinctive for their "promiscuous" gene expression, transcribing thousands of peripheral tissue genes (PTG) that are otherwise only expressed highly in one or two other organs. Much of this PTG expression by mTECs is controlled by the autoimmune regulator, AIRE. To determine the transcriptional impact of Kat7 loss, we purified mTECs and cTECs from Kat7-knockout and control mice and performed RNA-seq. The mTECs were further divided into MHCII-high and MHCII-low subsets.

2021-12-21 | GSE188870 | GEO

ATAC-seq profiling of medullary thymic epithelial cells from wildtype and Kat7-knockout mice

Project description:ATAC-seq profiling of medullary thymic epithelial cells from wildtype and Kat7-knockout mice

| PRJNA780541 | ENA

RNA-seq and ATAC-seq profiling of thymic epithelial cells from wildtype and Kat7 knockout mice

Project description:RNA-seq and ATAC-seq profiling of thymic epithelial cells from wildtype and Kat7 knockout mice

| PRJNA780536 | ENA

RNA-seq profiling of cortical and medullary thymic epithelial cells from wildtype and Kat7 knockout mice

Project description:RNA-seq profiling of cortical and medullary thymic epithelial cells from wildtype and Kat7 knockout mice

| PRJNA780539 | ENA

Transcription profiling of mouse fetal thymic organ culture BDC2.5 CD4+CD8+ thymocytes from B6g7 or NOD strain backgrounds following addition of the BDC mimotope peptide

Project description:Fetal thymic organ culture (FTOC) DC2.5 CD4+CD8+ thymocytes from B6g7 or NOD background. 0 or 16 hour after addition of the BDC mimitope

2007-12-04 | E-GEOD-2128 | biostudies-arrayexpress

Transcriptome analysis of conventional dendritic cells (cDCs) introduced into the thymic microenvironment of re-aggregated thymic organ cultures (RTOCs)

Project description:Transcriptome analysis of conventional dendritic cells (cDCs) introduced into the thymic microenvironment of re-aggregated thymic organ cultures (RTOCs)

| PRJNA689792 | ENA

Transcriptome analysis of conventional dendritic cells (cDCs) introduced into the thymic microenvironment of re-aggregated thymic organ cultures (RTOCs)

Project description:cDCs home from the periphery into the thymus. In order to determine the phenotypic and functional changes introduced by the thymic microenvironment to these thymus-homing cDCs, RNA-based next generation sequencing (RNAseq) was performed with splenic (sp-DC) and thymic conventional DCs (t-DCs) re-isolated from RTOCs after two days of culture. Methods: RTOCs were generated from single-cell suspensions of thymi isolated from E14.5 to E16.5 fetuses of Foxp3hCD2 reporter mice (BALB/c background), and sp‑DCs or t‑DCs sorted from 4-8 weeks old female CD45.1xBALB/c mice were introduced. After two days of culture, 1‑2x103 cDCs were re-isolated from RTOCs as CD45.1+Lin-CD11chi by FACS, and total RNA for transcriptional profiling by low-input RNAseq was isolated. Total RNA from sp-DC and t-DCs isolated ex vivo from 4-8 weeks old female CD45.1xBALB/c mice was used as control. RNAseq was performed on an Illumina HiSeq2500 system. Differential gene expression between the four different conditions was computed from the read counts. Results: The number of differentially expressed genes between ex vivo isolated sp-DC and t-DC was drastically reduced comparing sp-DCs and t-DCs re-isolated from RTOCs. This finding implies that the thymic microenvironment within an RTOC modulates the gene expression in sp‑DCs, conferring a transcriptomic profile that more closely resembled the one from t‑DCs. Conclusion: The thymic microenvironment modulates the transcriptome of thymus-homing peripheral cDCs.

2021-03-01 | GSE164280 | GEO

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