Integrative epigenetic analysis reveals AP-1 promotes activation of tumor-infiltrating regulatory T cells in HCC.

Regulatory T (Treg) cells that infiltrate human tumors exhibit stronger immunosuppressive activity compared to peripheral blood Treg cells (PBTRs), thus hindering the induction of effective antitumor immunity. Previous transcriptome studies have identified a set of genes that are conserved in tumor-infiltrating Treg cells (TITRs). However, epigenetic profiles of TITRs have not yet been completely deciphered. Here, we employed ATAC-seq and CUT&Tag assays to integrate transcriptome profiles and identify functional regulatory elements in TITRs. We observed a global difference in chromatin accessibility and enhancer landscapes between TITRs and PBTRs. We identified two types of active enhancer formation in TITRs. The H3K4me1-predetermined enhancers are poised to be activated in response to tumor microenvironmental stimuli. We found that AP-1 family motifs are enriched at the enhancer regions of TITRs. Finally, we validated that c-Jun binds at regulatory regions to regulate signature genes of TITRs and AP-1 is required for Treg cells activation in vitro. High c-Jun expression is correlated with poor survival in human HCC. Overall, our results provide insights into the mechanism of AP-1-mediated activation of TITRs and can hopefully be used to develop new therapeutic strategies targeting TITRs in liver cancer treatment.

Gene Selection for the Discrimination of Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer worldwide. Cancer discrimination is a typical application of gene expression analysis using a microarray technique. However, microarray data suffer from the curse of dimensionality and usual imbalanced class distribution between the majority (tumor samples) and minority (normal samples) classes. Feature gene selection is necessary and important for cancer discrimination. OBJECTIVES: To select feature genes for the discrimination of CRC. METHODS: We improve the feature selection algorithm based on differential evolution, DEFSw by using RUSBoost classifier and weight accuracy instead of the common classifier and evaluation measure for selecting feature genes from imbalance data. We firstly extract differently expressed genes (DEGs) from the CRC dataset of the TCGA and then select the feature genes from the DEGs using the improved DEFSw algorithm. Finally, we validate the selected feature gene sets using independent datasets and retrieve the cancer related information for these genes based on text mining through the Coremine Medical online database. RESULTS: We select out 16 single-gene feature sets for colorectal cancer discrimination and 19 single-gene feature sets only for colon cancer discrimination. CONCLUSIONS: In summary, we find a series of high potential candidate biomarkers or signatures, which can discriminate either or both of colon cancer and rectal cancer with high sensitivity and specificity.

An Integrated Approach for Identifying Molecular Subtypes in Human Colon Cancer Using Gene Expression Data.

Identifying molecular subtypes of colorectal cancer (CRC) may allow for more rational, patient-specific treatment. Various studies have identified molecular subtypes for CRC using gene expression data, but they are inconsistent and further research is necessary. From a methodological point of view, a progressive approach is needed to identify molecular subtypes in human colon cancer using gene expression data. We propose an approach to identify the molecular subtypes of colon cancer that integrates denoising by the Bayesian robust principal component analysis (BRPCA) algorithm, hierarchical clustering by the directed bubble hierarchical tree (DBHT) algorithm, and feature gene selection by an improved differential evolution based feature selection method (DEFSW) algorithm. In this approach, the normal samples being completely and exclusively clustered into one class is considered to be the standard of reasonable clustering subtypes, and the feature selection pays attention to imbalances of samples among subtypes. With this approach, we identified the molecular subtypes of colon cancer on the mRNA gene expression dataset of 153 colon cancer samples and 19 normal control samples of the Cancer Genome Atlas (TCGA) project. The colon cancer was clustered into 7 subtypes with 44 feature genes. Our approach could identify finer subtypes of colon cancer with fewer feature genes than the other two recent studies and exhibits a generic methodology that might be applied to identify the subtypes of other cancers.

Impaired function of the intestinal barrier in a novel sub-health rat model.

Sub-health is a state featuring a deterioration in physiological function between health and illness, and the sub-health condition has surfaced as life-threatening in humans. The aim of the present study was to establish a sub-health model in rats, and investigate the function of the intestinal barrier in the sub-health rats and rats following intervention. To establish a sub­health model, the rats were subjected to a high­fat and sugar diet, motion restriction and chronic stress. Their serum glucose and triglyceride levels, immune function and adaptability were then measured. The levels of diamine oxidase and D­lactic acid in the plasma were analyzed as markers of the intestinal permeability. The protein and mRNA expression levels of anti­apoptotic YWHAZ in the colonic tissue was detected using immunohistochemical and reverse transcription­quantitative polymerase chain reaction analyses In the present study, the sub­health rat model was successfully established, and sub­health factors increased the intestinal permeability and reduced the expression of YWHAZ. Providing sub­health rats with normal living conditions did not improve the function of the intestinal barrier. In conclusion, the results of the present study demonstrated that intestinal disorders in the sub­health rat model may result from the damage caused by reduce intestinal barrier function as well as the decreased expression levels of YWHAZ. Additionally, rats in the sub­health condition did not recover following subsequent exposure to normal living conditions, suggesting that certain exercises or medical intervention may be necessary to improve sub-health symptoms.