Transcriptomics,Genomics

Dataset Information

56

Dual role of Act1 in keratinocyte differentiation and host defense: TRAF3IP2 silencing alters keratinocyte differentiation while inhibiting IL-17 responses


ABSTRACT: TRAF3IP2 is a candidate psoriasis susceptibility gene encoding Act1, a ubiquitin ligase that couples the IL-17 receptor to downstream signaling pathways. We investigated the role of Act1 in keratinocyte responses to IL-17 using a tetracycline inducible shRNA targeting TRAF3IP2. Tet exposure for seven days effectively silenced TRAF3IP2 mRNA and Act1 protein, resulting in 761 genes with significant changes in expression (495 down, 266 up, >1.5-fold, p<0.05). Gene Ontology analysis revealed that genes affected by TRAF3IP2 silencing are involved in epidermal differentiation, with early differentiation genes (KRT1, KRT10, DSC1, DSG1) being downregulated and late differentiation genes (SPRR2, SPRR3, LCE3) being upregulated. AP1 binding sites were enriched upstream of genes up-regulated by TRAF3IP2 silencing. Correspondingly, nuclear expression of FosB and Fra1 was increased in TRAF3IP2-silenced cells. Many genes involved in host defense were induced by IL-17 in a TRAF3IP2-dependent fashion. Inflammatory differentiation conditions (serum addition for 4 days postconfluence) markedly amplified these IL-17 responses, while increasing basal levels and TRAF3IP2 silencing-dependent upregulation of late differentiation genes. These findings suggest that TRAF3IP2 may alter both epidermal homeostasis and keratinocyte defense responses to influence psoriasis risk. Overall design: Immortalized N/TERT-2G keratinocytes were either untreated or treated with tetracycline (TET) for TRAF3IP2 knockdown. Additionally, cells were either untreated or treated with IL17, TNF, or IL17+TNF. The experiment was replicated 4 times (batch IDs 2, 3, 4 and 5). A total of 32 samples were generated for RNA-seq analysis (8 treatments x 4 replicated experiments = 32 RNA-seq samples).

INSTRUMENT(S): Illumina Genome Analyzer IIx (Homo sapiens)

SUBMITTER: William R Swindell  

PROVIDER: GSE86451 | GEO | 2017-08-21

SECONDARY ACCESSION(S): PRJNA341946

REPOSITORIES: GEO

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Publications

Dual Role of Act1 in Keratinocyte Differentiation and Host Defense: TRAF3IP2 Silencing Alters Keratinocyte Differentiation and Inhibits IL-17 Responses.

Lambert Sylviane S   Swindell William R WR   Tsoi Lam C LC   Stoll Stefan W SW   Elder James T JT  

The Journal of investigative dermatology 20170306 7


TRAF3IP2 is a candidate psoriasis susceptibility gene encoding Act1, an adaptor protein with ubiquitin ligase activity that couples the IL-17 receptor to downstream signaling pathways. We investigated the role of Act1 in keratinocyte responses to IL-17 using a tetracycline inducible short hairpin RNA targeting TRAF3IP2. Tetracycline exposure for 7 days effectively silenced TRAF3IP2 mRNA and Act1 protein, resulting in 761 genes with significant changes in expression (495 down, 266 up; >1.5-fold,  ...[more]

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