Epigenetic modulation of Wnt signalling in the ageing human intestinal epithelium: consequences for tissue homeostasis

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The human gut, which is lined with finger-like invaginations called crypts, is continually being renewed. Each crypt is populated by cells derived from a small number of stem cells present at the bases of each crypt. The stem cells usually divide asymmetrically to produce one stem cell and one daughter cell, thus maintaining the stem cell population. The daughter cell divides symmetrically several more times while moving up the side of the crypt until, about halfway up, it stops dividing and differentiates into one of several cell types necessary for normal gut function. These cells become components of the gut surface, where they are programmed to die, and are shed into the faecal stream. The rates of cell division and migration and differentiation are very tightly controlled by the expression of several genes. We have previously shown that several of the genes controlling cell division, migration and differentiation are gradually switched off in the ageing human gut by the addition of methyl groups to the DNA sequences comprising these genes. Since the gut is lined with crypts, where all cells are derived from a small number of stem cells, any change to a stem cell, such as gene methylation, will be passed on to all its progeny and will represent a significant proportion of the population of cells within the crypt. This implies that cells in which these genes are switched off will not be uniformly distributed throughout the gut, but rather they will be localised to specific crypts, resulting in a mosaic pattern of affected crypts that may eventually be at increased risk of disease. We have previously found this to be true in elderly subjects. Here we aim to extend these observations to many more people of different ages, to determine if, as we predict, during ageing more and more of these important genes are switched off by methylation, and that this occurs in increasing numbers of crypts. We also aim to understand what happens in the crypts when these important genes are switched off in the stem cells. Do the cells divide more rapidly? Do they travel further up the crypt while still dividing? Are the cells more or less likely to differentiate into one type of cell or another? Are they more resistant to programmed cell death? The answers to these questions may help us to understand what is going wrong during the ageing process, and may provide insight into strategies for the prevention of age-related disease.