Epigenetics of aging and cancer

Transcriptional and epigenetic alterations during aging and cancer 

Aging is associated with defective organ maintenance and increased tissue dysfunction as well as with a higher risk for the development of pathological conditions, including cancer. Colorectal cancer is one of the most frequent and lethal neoplasms and its incidence exponentially increases with age. The focus of the Neri lab is the functional characterization of transcriptome and epigenome alterations that occur during adult stem cell aging in the intestinal system. The main aim is to characterize transcriptional and epigenetic alterations of stem cells during aging (focusing on DNA methylation changes together with principal histone modifications). The group employs genome-wide and single-cell technology to dissect alterations of the transcriptional and epigenetic landscape of the stem cells of the mouse small intestine and colon. Functional experiments are carried out by utilizing in vitro systems (intestinal organoids) and in vivo mouse models. In addition, the group has developed novel tools to identify dormant stem cells in intestine in vivo, to characterize in vitro organoid systems and to analyze DNA methylation in rare cells. 

Epigenetic drift and epigenetic clocks 

Several studies have demonstrated that intestinal stem cells represent the cells-of-origin of intestinal cancer and that clonal dominance of mutant stem cells appears frequently during aging. Emerging evidence indicates that genetic and epigenetic factors impact on the functionality and homeostasis of adult stem cells during aging, thereby favoring the selective advantage of dominant clones and the onset of cancer. Among these factors, DNA methylation (a stable and heritable epigenetic modification) has been associated with aging-induced diseases and cancer development. Recent discovery that DNA methylation can be actively removed by the TET proteins (ten-eleven-translocation) has revealed the importance of this epigenetic modification in several biological models. Epigenetic drift refers to the gradual and stochastic changes that occur in the epigenome over time. Epigenetic drift can occur naturally as a consequence of aging, as well as in response to environmental exposures and lifestyle choices. These changes can accumulate over the lifespan of an individual, leading to alterations in gene expression patterns, driving clonal selection and potentially contributing to age-related diseases and conditions. Our group identified an intestine-specific DNA methylation drift that is associated with colon cancer. We are currently studying the origin of this epigenetic drift and its consequences in cancer development.

Deciphering and counteracting Inflammaging. 

Inflammaging refers to a state of chronic low-grade inflammation that occurs with aging. We recently found that inflammaging is driven by upregulation of innate immune receptors and systemic interferon gamma (IFN gamma) signaling. Importantly, we found that inflammaging can be ameliorated by dietary restriction (DR) interventions in a tissue-specific manner. Moreover, DR ameliorates aging-induced alterations of chromatin accessibility and RNA transcription of the inflammaging gene network while failing to rescue those alterations on the rest of the genome. Our results present a comprehensive understanding of the molecular network regulating inflammation in aging and DR and provide anti-inflammaging therapeutic targets. In addition, we have further demonstrated that the intestinal epithelium shows this proinflammatory phenotype during aging and that it is lost following long in-vitro culturing suggesting that is driven by external factors (e.g. the gut microbiome) and that can be reverted (opening therapeutics opportunity). Moreover, we found that treating mice with an antibody anti-IFN can revert the intestinal inflammaging phenotype by rescuing the number of Lgr5+ intestinal stem cells (ISCs) and of Muc2+ Goblet cells (epithelial cells of the intestine responsible for the antimicrobial response) as well as the number of pro-inflammatory Cytotoxic Ccl5+ T-cells resident in the intestinal lamina propria to a young-like state. Importantly, pretreatment with anti-IFN antibody is able to improve the gut regeneration after treatment with the chemotherapeutic Fluorouracil (5FU) that induces intestinal damage as demonstrated by analysis of the mice body weight and histochemistry. Overall, our data indicate that inhibition of IFN can have beneficial effects in elderly with intestinal pathologies and/or that undergo chemotherapy. Indeed, for some cancers (e.g. colon cancer), the chemotherapeutic drug cocktail has very severe side effects and, very often, drugs are combined according to the patient’s health status.
 

Figure 2. During lifetime, adult stem cells accumulate epigenetic alterations that lead to the appearance and expansion of mutant stem cell clones. These cells lead to tissue dysfunction and cancer. Figure adapted from Ermolaeva, Neri, et al., Nature Reviews MCB, 2018.