Project description:Among vertebrate animals, mammals have retained a unique molecular change that allows an intracellular arrestin domain-containing protein to bind covalently to thioredoxin. This interaction of Thioredoxin-Interacting Protein (TXNIP) with thioredoxin can only occur when thioredoxin is in the reduced state, allowing TXNIP to "sense" the cellular oxidized environment1. Here we show that a single cysteine in TXNIP mediates the development of hepatic insulin resistance in the setting of a high fat diet (HFD). Mice with exchange of TXNIP Cysteine 247 for Serine (C247S) showed improved whole-body and hepatic insulin sensitivities compared to wildtype (WT) controls following an 8-week HFD. The inhibition of the TXNIP-thioredoxin interaction under chow and HFD also regulated plasma and liver lipids and reduced free fatty acid accumulation in the livers following HFD. These data show that mammals have a single amino acid enabling interaction of redox state with TXNIP that mediates insulin resistance in the setting of a high-fat diet. This reveals a potential evolutionarily-conserved mechanism for hepatic insulin resistance in metabolic syndromes.
Project description:To investigate the difference in bone remodeling between wild-type and Txnip knock-out mice. we extracted bone marrow from wild-type and Txnip knock-out mice and then screened them to get our interesting cells. We then used single-cell RNA sequencing (scRNA-seq) to analyze the selected bone marrow from wild-type and Txnip knock-out mice.
Project description:Chemotherapy, the standard of care treatment for cancer patients with advanced disease, has been increasingly recognised to activate host immune responses to produce durable outcomes. Here, in colorectal adenocarcinoma (CRC) we identify oxaliplatin-induced Thioredoxin Interacting Protein (TXNIP), a MondoA-dependent tumor suppressor gene, as a negative regulator of Growth/Differentiation Factor 15 (GDF15). GDF15 is a negative prognostic factor in CRC and promotes the differentiation of regulatory T cells (Tregs), which inhibit CD8 T cell activation. Intriguingly, multiple models including patient-derived tumor organoids demonstrate that the loss of TXNIP and GDF15 responsiveness to oxaliplatin is associated with advanced disease or chemotherapeutic resistance, with transcriptomic or proteomic GDF15/TXNIP ratios showing potential as a prognostic biomarker. These findings illustrate a potentially common pathway where chemotherapy-induced epithelial oxidative stress drives local immune remodelling for patient benefit, with disruption of this pathway seen in refractory or advanced cases.
Project description:To examine the generality of our finding where the gene expression profile of TXNIP knockout in MDA-MB-231 cells resembles of that Myc overexpression transcriptional program, our lab has generated TXNIP null HCC70 (HCC70:TKO) and MB135 (MB135:TKO) cells. We characterized the gene exrpession programs of these cells by RNA-seq.
Project description:Our RNA sequencing result demonstrated that TXNIP loss increased the levels of Myc-dependent transcription. To determine whether TXNIP regulates global Myc genomic occupancy, we performed Myc ChIP-seq on parental 231 and 231:TKO cells.
