Methylation reveals a niche: Stem cell succession in human colon crypts

Little it known about human stem cells although they are likely to be the earliest progenitors of carcinomas. Just as methylation can substitute for mutations to inactivate tumor suppressor genes, methylation can also substitute for mutations in a phylogenetic analysis. This review explains why stem cell dynamics may be important to tumor progression and how methylation patterns found in a normal human colon can be used to reconstruct the behavior of crypt stem cells. Histories are recorded in sequences and strategies used to reconstruct phylogenies from sequences likely apply to methylation patterns because both exhibit somatic inheritance. Such a quantitative analysis of colon methylation patterns infers stem cells live in niches containing multiple 'stem' cells. Although niche stem cell numbers remain constant, clonal succession is inherent to niches because periodically progeny from a single stem cell become dominant. These niche succession cycles may potentially accumulate multiple alterations because they resemble superficially the clonal succession of tumor progression except that they occur invisibly in the absence of selection or phenotypic change. Alterations without immediate selective value may hitchhike passively in the stem cells that become dominant during niche succession cycles. The inherent ability of a niche to fix alterations (Muller's ratchet) is another potential mechanism besides instability and selection to sequentially accumulate multiple alterations. Many alterations found in colorectal tumors may reflect such occult clonal progression in normal colon.