Chromatin organizer SATB1 controls the cell identity of CD4+ CD8+ double-positive thymocytes by compacting super-enhancers
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ABSTRACT:
PROVIDER: PRJNA758699 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15663800_1.fastq.gz | Fastqsanger.gz | |||
| SRR15663800_2.fastq.gz | Fastqsanger.gz | |||
| SRR15663801_1.fastq.gz | Fastqsanger.gz | |||
| SRR15663801_2.fastq.gz | Fastqsanger.gz | |||
| SRR15663802_1.fastq.gz | Fastqsanger.gz |
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Project description:CD4+ and CD8+ double-positive (DP) thymocytes are at a critical stage during the T cell development in thymus. DP cells rearrange the T cell receptor gene Tcra to generate T cell receptors with TCR. Then DP cells differentiate into CD4 or CD8 single-positive (SP) thymocytes, Regulatory T cells, or invariant nature kill T cells (iNKT) according to the TCR signal. Chromatin organizer SATB1 is highly expressed in DP cells and plays an essential role in regulating Tcra rearrangement and differentiation of DP cells. Here we explored the mechanism of SATB1 orchestrating gene expression in DP cells. Single-cell RNA sequencing assay of SATB1-deficient thymocytes showed that the cell identity of DP thymocytes was changed, and the genes specifically highly expressed in DP cells were down-regulated. ChIP-seq and ATAC-seq data showed the similar tendency. The super-enhancers regulate the expressions of the DP-specific genes, and the SATB1 deficiency reduced the super-enhancer activity. Hi-C data showed that interactions in super-enhancers and between super-enhancers and promoters decreased in SATB1 deficient thymocytes. We further explored the regulation mechanism of two SATB1-regulating genes, ETS2 and Bcl6, in DP cells and found that the knockout of the super-enhancers of these two genes impaired the development of DP cells. Our research reveals that SATB1 globally regulates super-enhancers of DP cells and promotes the establishment of DP cell identity, which helps understand the role of SATB1 in thymocyte development.
2021-09-02 | GSE182995 | GEO
Project description:T-cell receptor (TCR) signaling by MHC class-I and -II induces thymocytes to acquire cytotoxic and helper fates via induction of Runx3 or ThPOK transcription factors, respectively. The mechanisms by which TCR signaling is translated into transcriptional programs for each cell fate remain elusive. We show that a genome organizer, Satb1, activates genes for lineage-specifying factors, including ThPOK and Runx3, in post-selection thymocytes. Indeed, Satb1-deficient thymocytes are partially redirected to inappropriate T lineages after MHC selection. Although Satb1 is dispensable for maintaining ThPOK in CD4+ T cells, it is necessary for restraining expression of the Treg factor FoxP3. Collectively, our findings demonstrate that Satb1 shapes the primary T-cell pool by initially directing lineage-specific transcriptional programs and subsequently balancing effector versus regulatory subsets via FoxP3 repression.
2017-01-19 | GSE77000 | GEO
Project description:CD4+ and CD8+ double-positive (DP) thymocytes play a crucial role in T cell development in the thymus. DP cells rearrange the T cell receptor gene Tcra to generate T cell receptors with TCRβ. DP cells differentiate into CD4 or CD8 single-positive (SP) thymocytes, regulatory T cells, or invariant nature kill T cells (iNKT) in response to TCR signaling. Chromatin organizer SATB1 is highly expressed in DP cells and is essential in regulating Tcra rearrangement and differentiation of DP cells. Here we explored the mechanism of SATB1 orchestrating gene expression in DP cells. Single-cell RNA sequencing shows that Satb1 deletion changes the cell identity of DP thymocytes and down-regulates genes specifically and highly expressed in DP cells. Super-enhancers regulate the expressions of DP-specific genes, and our Hi-C data show that SATB1 deficiency in thymocytes reduces super-enhancer activity by specifically decreasing interactions among super-enhancers and between super-enhancers and promoters. Our results reveal that SATB1 plays a critical role in thymocyte development to promote the establishment of DP cell identity by globally regulating super-enhancers of DP cells at the chromatin architectural level.
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Project description:T-cell receptor (TCR) signaling by MHC class-I and -II induces thymocytes to acquire cytotoxic and helper fates via induction of Runx3 or and ThPOK transcription factors, respectively. The mechanisms by The mechanisms by which TCR signaling is translated into transcriptional programs for each cell fate remain elusive. It remains elusivewhich how TCR signaling is translated into transcriptional programs for each cell fate remain elusive. We show that a genome organizer, SATB1, activates genes for lineage-specifying factors, including ThPOK, Runx3, CD4, CD8 and Treg factor Foxp3, and Treg factor Foxp3, and CD4, and /CD8, in post-selection thymocytes. Indeed, SATBatb1-deficient thymocytes are partially redirected into inappropriate T lineages after both MHC class-I and -II mediated selection, and fail to generate Treg subset. Despite its essential role in initiating regulatory regions activity in TCR signaled thymocytes. SATBatb1 is becomes dispensable for maintaining ThPOK in CD4+ T cells. Collectively, our findings demonstrate that SATBatb1 shapes the primary T-cell pool by initially directing lineage-specific transcriptional programs in the thymus.
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Project description:Rag1 and Rag2 gene expression in CD4+CD8+ double positive (DP) thymocytes depends on the activity of a distant anti-silencer element (ASE) that counteracts the activity of an intergenic silencer. However, the mechanistic basis for ASE activity is unknown. Here we show that the ASE physically interacts with the distant Rag1 and Rag2 gene promoters in DP thymocytes, bringing the two promoters together to form an active chromatin hub. Moreover, we show that the ASE functions as a classical enhancer that can potently activate these promoters in the absence of the silencer or other locus elements. In thymocytes lacking the chromatin organizer SATB1, we identified a partial defect in Tcra gene rearrangement that was associated with reduced expression of Rag1 and Rag2 at the DP stage. SATB1 binds to the ASE and Rag promoters, facilitating inclusion of Rag2 in the chromatin hub and the loading of RNA polymerase II to both the Rag1 and Rag2 promoters. Our results provide a novel framework for understanding ASE function and demonstrate a novel role for SATB1 as a regulator of Rag locus organization and gene expression in DP thymocytes. Sequencing of Satb1-ChIP and input control from 6 wk old thymus
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Project description:Hematopoietic stem cells (HSCs) are now recognized as a heterogeneous population in self-renewing and differentiation capabilities. However, fundamental mechanisms governing the heterogeneity remain uncertain. We here show that special AT-rich sequence-binding protein 1 (SATB1), a global chromatin organizer, is involved in the mechanisms. Analyzing hematological lineage-restricted SATB1 knock out mice proved that SATB1 is indispensable for both self-renewal and normal differentiation of adult HSCs. Using SATB1/Tomato knock-in mice, we subdivided HSCs according to SATB1 intensity. Culture experiments and RNA-sequencing revealed essential differences between SATB1- and SATB1+ HSCs regarding lineage potential.
2018-06-14 | GSE94630 | GEO
Project description:Rag1 and Rag2 gene expression in CD4+CD8+ double positive (DP) thymocytes depends on the activity of a distant anti-silencer element (ASE) that counteracts the activity of an intergenic silencer. However, the mechanistic basis for ASE activity is unknown. Here we show that the ASE physically interacts with the distant Rag1 and Rag2 gene promoters in DP thymocytes, bringing the two promoters together to form an active chromatin hub. Moreover, we show that the ASE functions as a classical enhancer that can potently activate these promoters in the absence of the silencer or other locus elements. In thymocytes lacking the chromatin organizer SATB1, we identified a partial defect in Tcra gene rearrangement that was associated with reduced expression of Rag1 and Rag2 at the DP stage. SATB1 binds to the ASE and Rag promoters, facilitating inclusion of Rag2 in the chromatin hub and the loading of RNA polymerase II to both the Rag1 and Rag2 promoters. Our results provide a novel framework for understanding ASE function and demonstrate a novel role for SATB1 as a regulator of Rag locus organization and gene expression in DP thymocytes.
2015-02-25 | GSE66248 | GEO
Project description:Mechanisms of tissue-specific gene expression regulation, particularly via spatial coordination of gene promoters and their regulatory elements are poorly understood. Here we investigated the 3D genome organization of developing murine T cells. We identified a tissue-specific genome organizer SATB1 as a factor enriched at the anchors of promoter-enhancer chromatin loops. To unravel its functions in T cells, we generated Satb1fl/flCd4-Cre+ (Satb1 cKO) conditional knockout animals. Satb1 cKO animals suffer from severe autoimmunity so we sought to investigate a potential link between the autoimmunity and putatively deregulated nuclear architecture caused by SATB1 depletion. This series of Hi-C and HiChIP experiments is a part of SuperSeries including also RNA-Seq and ATAC-Seq experiments to fully understand the deregulation of Satb1 cKO thymocytes and to unravel the roles of SATB1 in T cell chromatin organization. Utilizing the HiChIP data, we compared SATB1 and CTCF-mediated chromatin loops, revealing that SATB1 builds a more refined layer of genome organization upon the CTCF scaffold. Moreover, H3K27ac HiChIP and Hi-C experiments in WT and Satb1 cKO thymocytes helped us to assess the functional impact of SATB1 and its underlying genome-wide regulome. SATB1 primarily mediates promoter-enhancer loops affecting a number of master regulator genes whose deregulation in knockout animals may comprise a cell-intrinsic mechanism of the autoimmunity. Our findings indicate a possible existence of a special class of genome organizers controlling tissue and/or time-specific transcriptional programs via spatial chromatin arrangements that are complementary to the function of conventional ubiquitously expressed genome organizers.
2022-09-23 | GSE173446 | GEO
Project description:Trophoblast stem (TS) cell renewal and differentiation are essential processes in placentation. Here, we have identified the mechanism/targets of chromatin organizer/transcription factor called special AT-rich binding protein 1 (SATB1) action on TS cell renewal by RNA-seq analysis in Rcho-1 TS cells expressing Satb1 shRNAs.
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Project description:Mechanisms of tissue-specific gene expression regulation, particularly via spatial coordination of gene promoters and their regulatory elements are poorly understood. Here we investigated the 3D genome organization of developing murine T cells. We identified a tissue-specific genome organizer SATB1 as a factor enriched at the anchors of promoter-enhancer chromatin loops. To unravel its functions in T cells, we generated Satb1fl/flCd4-Cre+ (Satb1 cKO) conditional knockout animals. Satb1 cKO animals suffer from severe autoimmunity so we sought to investigate a potential link between the autoimmunity and putatively deregulated nuclear architecture caused by SATB1 depletion. This series of RNA-Seq experiments is a part of SuperSeries including also ATAC-Seq, Hi-C and HiChIP experiments to fully understand the deregulation of Satb1 cKO thymocytes and to unravel the roles of SATB1 in T cell chromatin organization. RNA-Seq experiments supported the repressive nature of Satb1 cKO nuclear environment and together with the other datasets it showed that SATB1 functions primarily as an activator. SATB1 mediates promoter-enhancer chromatin loops affecting a number of master regulator genes whose deregulation in knockout animals may comprise a cell-intrinsic mechanism of the autoimmunity. Our findings indicate a possible existence of a special class of genome organizers controlling tissue and/or time-specific transcriptional programs via spatial chromatin arrangements that are complementary to the function of conventional and ubiquitously expressed genome organizers.
2022-09-23 | GSE173470 | GEO