Editors' ChoiceCancer and Stem Cells

Methylation Balancing Act

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Science Translational Medicine  10 Feb 2010:
Vol. 2, Issue 18, pp. ec20
DOI: 10.1126/scitranslmed.3000921

Stem cells are the celebrities of modern medical science, holding great promise for diseases that remain incurable. To take full advantage of stem cells’ potential, a deep understanding of their role in balancing cellular proliferation and differentiation is paramount. The players involved in the regulation of this process have remained elusive.

One common feature of malignancies is the inability of somatic cells to complete the differentiation process. Epigenetic silencing has been implicated in this process, but now Sen et al. provide evidence that, in epidermal tissue, self-renewal is a dynamic process in which methylation-induced silencing of the differentiation program involves concerted actions by a DNA methylating enzyme, DNMT1, and a DNA methylation targeting protein, UHRF, and the differentiated state is promoted by a DNA stress response protein, GADD45. Using ex vivo grafts derived from human skin cells, the authors show that DNMT1 protein and RNA are expressed exclusively in progenitor cells within the basal layer and not in terminally differentiated cells. Genetic knockdown of DNMT1 expression caused premature differentiation and loss of tissue self-renewal and was confirmed in vivo to be progenitor cell–specific and not due to global tissue failure. These results were consistent with global gene-expression profiles in DNMT1-deficient cells that showed an epidermal gene expression program compatible with a role in sustaining proliferation and repressing differentiation. Methylated DNA immunoprecipitation in undifferentiated and differentiated keratinocytes followed by hybridization to promoter tiling arrays provided evidence that genes methylated by DNMT1 in undifferentiated progenitor cells lost promoter methylation after terminal differentiation.

The authors investigate the mechanism for impaired proliferation associated with DNMT1, identify reciprocal balancing effects induced by GADD45, and posit that the imbalance of these two methylating forces may offer insight to the etiology of epithelial cancers, highlighting an avenue for intervention.

G.-L. Sen et al., DNMT1 maintains progenitor function in self-renewing somatic tissue. Nature 463, 563–567 (2010). [Abstract]

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