MFAG 2021 - Origin of the aging-associated intestinal epigenetic drift.
Partecipanti al progetto
- Neri Francesco (Responsabile)
Descrizione del progetto
Growing evidence points out that DNA methylation (DNAm) alterations, which accumulate with age, are associated with cancer insurgence (Zheng et al., Epigenomics, 2016). However, still little is known on how the age-dependent DNAm changes are mechanistically originated and whether they have a functional role in driving cancer initiation. We have recently identified and characterized a cell-intrinsic, tissue-specific (intestine), proliferation-independent DNAm drift in intestinal stem cells (ISCs) during aging that mainly involves promoter hypermethylation of a specific group of genes (manuscript in preparation).
Differently from the CpG island methylator phenotype (CIMP) that is specific of a minor fraction of colon cancers (Toyota et al, PNAS, 1999), this novel DNAm drift is strongly expanded in all human colon cancer types (Figure 1A,B).
In this proposal, I aim to study this Aging- and Colon Cancer-Associated epigenetic drift (named here ACCA drift) to understand its impact in the initial phases of cellular transformation. The underlying hypothesis, supported by our preliminary results, is that intestinal stem cells with high ACCA drift may represent the cell of origin of intestinal cancers.
The major goals of the project are:
1) to mechanistically understand the origin of this stem cell epigenetic drift and
2) to functionally analyse the impact of ACCA drift on cancer initiation.