Epigenetic Age Acceleration and Change in Frailty in MOBILIZE Boston

Age-associated changes in DNA methylation have been implicated as one mechanism to explain the development of frailty, however previous cross-sectional studies of epigenetic age acceleration (eAA) and frailty have had inconsistent findings. Few longitudinal studies have considered the association of eAA with change in frailty. We sought to determine the association between eAA and change in frailty in the MOBILIZE Boston cohort. Participants were assessed at two visits 12-18 months apart. Intrinsic, extrinsic, GrimAge, and PhenoAge eAA were assessed from whole blood DNA methylation at baseline using the Infinium 450k array. Frailty was assessed by a continuous frailty score based on the frailty phenotype and by frailty index (FI). Analysis was by correlation and linear regression with adjustment for age, sex, smoking status, and BMI. 395 participants with a frailty score and 431 with a FI had epigenetic and follow-up frailty measures. For the frailty score and FI cohorts, respectively, mean (SD) ages were 77.8 (5.49) and 77.9 (5.47), 232 (58.7%) and 257 (59.6%) were female. All participants with epigenetic data identified as white. Baseline frailty score was not correlated with intrinsic or extrinsic eAA, but was correlated with PhenoAge and, even after adjustment for covariates, GrimAge. Baseline FI was correlated with extrinsic, GrimAge, and PhenoAge eAA with and without adjustment. No eAA measure was associated with change in frailty, with or without adjustment. Our results suggest that no eAA measure was associated with change in frailty. Further studies should consider longer periods of follow-up and repeated eAA measurement.

DNA Methylation-Driven Genes for Developing Survival Nomogram for Low-Grade Glioma

Low-grade gliomas (LGG) are heterogeneous, and the current predictive models for LGG are either unsatisfactory or not user-friendly. The objective of this study was to establish a nomogram based on methylation-driven genes, combined with clinicopathological parameters for predicting prognosis in LGG. Differential expression, methylation correlation, and survival analysis were performed in 516 LGG patients using RNA and methylation sequencing data, with accompanying clinicopathological parameters from The Cancer Genome Atlas. LASSO regression was further applied to select optimal prognosis-related genes. The final prognostic nomogram was implemented together with prognostic clinicopathological parameters. The predictive efficiency of the nomogram was internally validated in training and testing groups, and externally validated in the Chinese Glioma Genome Atlas database. Three DNA methylation-driven genes, ARL9, CMYA5, and STEAP3, were identified as independent prognostic factors. Together with IDH1 mutation status, age, and sex, the final prognostic nomogram achieved the highest AUC value of 0.930, and demonstrated stable consistency in both internal and external validations. The prognostic nomogram could predict personal survival probabilities for patients with LGG, and serve as a user-friendly tool for prognostic evaluation, optimizing therapeutic regimes, and managing LGG patients.

A Genome-Wide Investigation of Effects of Aberrant DNA Methylation on the Usage of Alternative Promoters in Hepatocellular Carcinoma

BackgroundThe alternative usage of promoters provides a way to regulate gene expression, has a significant influence on the transcriptome, and contributes to the cellular transformation of cancer. However, the function of alternative promoters (APs) in hepatocellular carcinoma (HCC) has not been systematically studied yet. In addition, the potential mechanism of regulation to the usage of APs remains unclear. DNA methylation, one of the most aberrant epigenetic modifications in cancers, is known to regulate transcriptional activity. Whether DNA methylation regulates the usage of APs needs to be explored. Here, we aim to investigate the effects of DNA methylation on usage of APs in HCC.MethodsPromoter activities were calculated based on RNA-seq data. Functional enrichment analysis was implemented to conduct GO terms. Correlation tests were used to detect the correlation between promoter activity and methylation status. The LASSO regression model was used to generate a diagnostic model. Kaplan–Meier analysis was used to compare the overall survival between high and low methylation groups. RNA-seq and whole-genome bisulfite sequencing (WGBS) in HCC samples were performed to validate the correlation of promoter activity and methylation.ResultsWe identified 855 APs in total, which could be well used to distinguish cancer from normal samples. The correlation of promoter activity and DNA methylation in APs was observed, and the APs with negative correlation were defined as methylation-regulated APs (mrAPs). Six mrAPs were identified to generate a diagnostic model with good performance (AUC = 0.97). Notably, the majority of mrAPs had CpG sites that could be used to predict clinical outcomes by methylation status. Finally, we verified 85.6% of promoter activity variation and 92.3% of methylation changes in our paired RNA-seq and WGBS samples, respectively. The negative correlation between promoter activity and methylation status was further confirmed in our HCC samples.ConclusionThe aberrant methylation status plays a critical role in the precision usage of APs in HCC, which sheds light on the mechanism of cancer development and provides a new insight into cancer screening and treatment.

IL-33 regulates age-dependency of long-term immune dysfunction induced by sepsis

Sepsis survival in adults is commonly followed by immunosuppression and increased susceptibility to secondary infections. However, the long-term immune consequences of pediatric sepsis are unknown. Here, we compared the frequency of Tregs, the activation of the IL-33/ILC2s axis in M2 macrophages, and the DNA methylation of epithelial lung cells from post-septic infant and adult mice. In contrast to adults, infant mice were resistant to secondary infection and did not show impairment in tumour controls upon melanoma challenge. Mechanistically, increased IL-33 levels, Tregs expansion, and activation of ILC2s and M2-macrophages were observed in post-septic adults but not infant mice. Impaired IL-33 production in post-septic infant mice was associated with increased DNA-methylation on lung epithelial cells. Notably, IL-33 treatment boosted the expansion of Tregs and induced immunosuppression in infant mice. Clinically, adults but not pediatric post-septic patients exhibited higher counts of Tregs and sera IL-33 levels. Hence, we describe a crucial and age-dependent role for IL-33 in post-sepsis immunosuppression.