IFNγ-Stat1 axis drives aging-associated loss of intestinal tissue homeostasis and regeneration.

The influence of aging on intestinal stem cells and their niche can explain underlying causes for perturbation in their function observed during aging. Molecular mechanisms for such a decrease in the functionality of intestinal stem cells during aging remain largely undetermined. Using transcriptome-wide approaches, our study demonstrates that aging intestinal stem cells strongly upregulate antigen presenting pathway genes and over-express secretory lineage marker genes resulting in lineage skewed differentiation into the secretory lineage and strong upregulation of MHC class II antigens in the aged intestinal epithelium. Mechanistically, we identified an increase in proinflammatory cells in the lamina propria as the main source of elevated interferon gamma (IFNγ) in the aged intestine, that leads to the induction of Stat1 activity in intestinal stem cells thus priming the aberrant differentiation and elevated antigen presentation in epithelial cells. Of note, systemic inhibition of IFNγ-signaling completely reverses these aging phenotypes and reinstalls regenerative capacity of the aged intestinal epithelium.

Antisense lncRNA CHROMR is linked to glioma patient survival.

Background: Natural non-coding antisense transcripts (ncNATs) are long non-coding RNAs (lncRNA) transcribed from the opposite strand of a separate protein coding or non-coding gene. As such, ncNATs can increase overlapping mRNA (and the coded protein) levels by stabilizing mRNA, absorbing inhibitory miRNAs and protecting the mRNA from degradation, or conversely decrease mRNA (or protein) levels by directing the mRNA towards degradation or inhibiting protein translation. Recently, growing numbers of ncNATs were shown to be dysregulated in cancerous cells, however, actual impact of ncNATs on cancer progression remains largely unknown. We therefore investigated gene expression levels of natural antisense lncRNA CHROMR (Cholesterol Induced Regulator of Metabolism RNA) and its sense protein coding gene PRKRA (Protein Activator of Interferon Induced Protein Kinase EIF2AK2) in gliomas. Next, we checked CHROMR effect on the survival of glioma patients. Methods: We performed RNA-seq on post-surgical tumor samples from 26 glioma patients, and normal brain tissue. Gene expression in TPM values were extracted for CHROMR and PRKRA genes. These data were validated using the TCGA and GTEx gene expression databases. Results: The gene expression level of ncNAT lncRNA CHROMR in glioma tissue was significantly higher compared to healthy brain tissue, while the expression of its sense counterpart protein coding PRKRA mRNA did not differ between glioma and healthy samples. Survival analysis showed lower survival rates in patients with low mRNA PRKRA/lncRNA CHROMR gene expression ratio compared to high ratio showing a link between lncRNA CHROMR and glioma patient survival prognosis. Conclusion: Here we show that elevated levels of lncRNA CHROMR (i.e., low ratio of mRNA PRKRA/lncRNA CHROMR) is associated with poor prognosis for glioma patients.

Establishment and evaluation of module-based immune-associated gene signature to predict overall survival in patients of colon adenocarcinoma.

BACKGROUND: Patients with colon adenocarcinoma (COAD) exhibit significant heterogeneity in overall survival. The current tumor-node-metastasis staging system is insufficient to provide a precise prediction for prognosis. Identification and evaluation of new risk models by using big cancer data may provide a good way to identify prognosis-related signature. METHODS: We integrated different datasets and applied bioinformatic and statistical methods to construct a robust immune-associated risk model for COAD prognosis. Furthermore, a nomogram was constructed based on the gene signature and clinicopathological features to improve risk stratification and quantify risk assessment for individual patients. RESULTS: The immune-associated risk model discriminated high-risk patients in our investigated and validated cohorts. Survival analyses demonstrated that our gene signature served as an independent risk factor for overall survival and the nomogram exhibited high accuracy. Functional analysis interpreted the correlation between our risk model and its role in prognosis by classifying groups with different immune activities. Remarkably, patients in the low-risk group showed higher immune activity, while those in the high-risk group displayed a lower immune activity. CONCLUSIONS: Our study provides a novel tool that may contribute to the optimization of risk stratification for survival and personalized management of COAD.

Single-cell atlas of the aging mouse colon.

We performed massive single-cell sequencing in the aging mouse colonic epithelium and immune cells. We identified novel compartment-specific markers as well as dramatic aging-associated changes in cell composition and signaling pathways, including a shift from absorptive to secretory epithelial cells, depletion of naive lymphocytes, and induction of eIF2 signaling. Colon cancer is one of the leading causes of death within the western world, incidence of which increases with age. The colonic epithelium is a rapidly renewing tissue, tasked with water and nutrient absorption, as well as hosting intestinal microbes. The colonic submucosa is populated with immune cells interacting with and regulating the epithelial cells. However, it is unknown whether compartment-specific changes occur during aging and what impact this would cause. We show that both epithelial and immune cells differ significantly between colonic compartments and experience significant age-related changes in mice. We found a shift in the absorptive-secretory cell balance, possibly linked to age-associated intestinal disturbances, such as malabsorption. We demonstrate marked changes in aging immune cells: population shifts and interactions with epithelial cells, linking cytokines (Ifn-γ, Il1B) with the aging of colonic epithelium. Our results provide new insights into the normal and age-associated states of the colon.

Intestinal stem cells heterogeneity and clonal dominance during aging: two faces of the same coin?

Intestinal epithelium undergoes dysfunctions and diseases over time with an exponential increase in the elderly population. Recent studies reported that the intestinal stem cells (ISCs) show a functional decline during aging and a lack of an appropriate cell identity control. Increase of cell-to-cell heterogeneity is a hallmark of aging tissues and organs, however there is little experimental evidence with regard to the cell heterogeneity of the ISCs. On the other hand, the ISCs continuously experience a niche clonality process that diminishes the initial cell heterogeneity over time. In this review, we discuss the latest findings on these topics focusing on the potential mechanisms driving intestinal stem cell heterogeneity and clonality during aging.