Reversing SKI–SMAD4-mediated suppression is essential for TH17 cell differentiation [ChIP-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE101593 | GEO | 2017/10/25
SECONDARY ACCESSION(S): PRJNA394907
REPOSITORIES: GEO
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Project description:Disruption of Ski/Smad4 license Th17 differentiation. TGF-b-Ski-Smad4-RORgt-Th17 axis
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Project description:T helper 17 (TH17) cells are critically involved in host defence, inflammation, and autoimmunity. Transforming growth factor ? (TGF?) is instrumental in TH17 cell differentiation by cooperating with interleukin-6 (refs 6, 7). Yet, the mechanism by which TGF? enables TH17 cell differentiation remains elusive. Here we reveal that TGF? enables TH17 cell differentiation by reversing SKI-SMAD4-mediated suppression of the expression of the retinoic acid receptor (RAR)-related orphan receptor ?t (ROR?t). We found that, unlike wild-type T cells, SMAD4-deficient T cells differentiate into TH17 cells in the absence of TGF? signalling in a ROR?t-dependent manner. Ectopic SMAD4 expression suppresses ROR?t expression and TH17 cell differentiation of SMAD4-deficient T cells. However, TGF? neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the Rorc locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGF? stimulation. SKI controls histone acetylation and deacetylation of the Rorc locus and TH17 cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the Rorc locus, Rorc expression, and TH17 cell differentiation in a SMAD4-dependent manner. Therefore, TGF?-induced disruption of SKI reverses SKI-SMAD4-mediated suppression of ROR?t to enable TH17 cell differentiation. This study reveals a critical mechanism by which TGF? controls TH17 cell differentiation and uncovers the SKI-SMAD4 axis as a potential therapeutic target for treating TH17-related diseases.
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Project description:Smad4 was required for febrile temperature enhanced Th17 differentiation. In order to further understand the mechanisms whereby Smad4 enhance Th17 differentiation, we conducted ChIP-seq analysis of Smad4 in Th17 cells cutured 37°C and 39.5°C after 24 hours.
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Project description:Initially identified as a functional marker for resident-memory (Trm) CD8+ T cells, CD103 (encoded by ITGAE gene) has broad roles in immunity and diseases. Elucidating the function and regulation of CD103 is thus of importance. This study revealed that the CD103 expression by CD8 T cells under steady state contributes to the clearance of acute viral infection. More importantly, it discovered TGF-SKI-Smad4 a critical signaling axis in restricting CD103 expression in CD8+ T cells for their function. Mechanistically, by ChIP-Seq and ChIP analysis, SKI associated with Smad4 was found to directly and epigenetically suppress CD103 transcription. This study therefore reveals a novel TGF-SKI-Smad4 pathway to specifically enable CD103 expression in CD8+ T cells for protective immunity.
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Project description:RORgt is known to instruct the differentiation of Th17 cells that mediate the pathogenesis of autoimmune diseases. However, it remains unknown whether RORgt plays a distinct role in the differentiation and effector function of Th17 cells. Here we show that mutation of RORgt lysine 256, a ubiquitination site, to arginine (K256R) separates the RORgt role in these two functions. Preventing ubiquitination at K256 via arginine substitution does not affect RORgt-dependent thymocyte development and Th17 differentiation in vitro and in vivo, however, greatly impaired the pathogenesis of Th17 cell-mediated experimental autoimmune encephalomyelitis (EAE). Mechanistically, K256R mutation impairs RORgt to bind to and activate Runx1 expression critical for Th17-mediated EAE. Thus, RORgt regulates the effector function of Th17 cells in addition to Th17 differentiation. This work informs the development of RORgt-based therapies that specifically target the effector function of Th17 cells responsible for autoimmunity.
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Project description:RORgt is known to instruct the differentiation of Th17 cells that mediate the pathogenesis of autoimmune diseases. However, it remains unknown whether RORgt plays a distinct role in the differentiation and effector function of Th17 cells. Here we show that mutation of RORgt lysine 256, a ubiquitination site, to arginine (K256R) separates the RORgt role in these two functions. Preventing ubiquitination at K256 via arginine substitution does not affect RORgt-dependent thymocyte development and Th17 differentiation in vitro and in vivo, however, greatly impaired the pathogenesis of Th17 cell-mediated experimental autoimmune encephalomyelitis (EAE). Mechanistically, K256R mutation impairs RORgt to bind to and activate Runx1 expression critical for Th17-mediated EAE. Thus, RORgt regulates the effector function of Th17 cells in addition to Th17 differentiation. This work informs the development of RORgt-based therapies that specifically target the effector function of Th17 cells responsible for autoimmunity.
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Project description:Th17 cells are a helper cell subset of pro-inflammatory T cells, which have diverse functions ranging from neutrophilic-inflammatory responses against pathogens to driving a number of autoimmune diseases. Accumulating evidence indicates that specific cellular lipid metabolic pathways that include fatty acid or cholesterol play an essential role in regulating the differentiation and function of Th17 cells. However, what molecular mechanisms link lipid metabolism and RORgt function during Th17-cell differentiation? By using a combination of a CRISPR- based screening system and a global lipidome analysis, we addressed this question in an effort to identify a specific lipid metabolite that is essential for RORgt-mediated Th17-cell differentiation. We found five lipid enzymes that elicit RORgt activity and constitute a core molecular signature of Th17 cells. Furthermore, although Th17 cells treated with TOFA, which is a ACC1 inhibitor, showed decreased mRNA expression of Th17 specific gene and chromatin accessibility at Th17 cell specific gene loci, we also found that extrinsic supplementation of LPE (1-18:1) restored the phenotype of ACC1-inhibited Th17 cells. Taken together, these series of results indicated that LPE (1-18:1) synthesized from the five lipid metabolic enzymes was required for RORgt to function appropriately in Th17-cell differentiation.
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