DNMT1 maintains progenitor function in self-renewing somatic tissue

Abstract

Progenitor cells maintain self-renewing tissues throughout life by sustaining their capacity for proliferation while suppressing cell cycle exit and terminal differentiation1,2. DNA methylation3,4,5 provides a potential epigenetic mechanism for the cellular memory needed to preserve the somatic progenitor state through repeated cell divisions. DNA methyltransferase 1 (DNMT1)6,7 maintains DNA methylation patterns after cellular replication. Although dispensable for embryonic stem cell maintenance,8 a clear role for DNMT1 in maintaining the progenitor state in constantly replenished somatic tissues, such as mammalian epidermis, is unknown. Here we show that DNMT1 is essential for epidermal progenitor cell function. DNMT1 protein was found enriched in undifferentiated cells, where it was required to retain proliferative stamina and suppress differentiation. In tissue, DNMT1 depletion led to exit from the progenitor cell compartment, premature differentiation and eventual tissue loss. Genome-wide analysis revealed that a significant portion of epidermal differentiation gene promoters were methylated in self-renewing conditions but were subsequently demethylated during differentiation. Furthermore, we show that UHRF1,9,10 a component of the DNA methylation machinery that targets DNMT1 to hemi-methylated DNA, is also necessary to suppress premature differentiation and sustain proliferation. In contrast, Gadd45A11,12 and B13, which promote active DNA demethylation, are required for full epidermal differentiation gene induction. These data demonstrate that proteins involved in the dynamic regulation of DNA methylation patterns are required for progenitor maintenance and self-renewal in mammalian somatic tissue.

Epigenetic regulation of aging stem cells

“…This review will focus primarily on changes in histone modifications. However, we also note that regulators of DNA methylation are required for the function of a variety of adult stem cells (Zhao et al, 2003;Ma et al, 2009;Trowbridge et al, 2009;Sen et al, 2010;Trowbridge and Orkin, 2010;Wu et al, 2010), and that they complex with chromatin modifiers to elicit changes in chromatin state (Jones et al, 1998;Nan et al, 1998;Fuks et al, 2003). In addition, chromatin remodeling factors are also important for stem and progenitor cell function (Lessard et al, 2007;Ho et al, 2009;Ho and Crabtree, 2010), suggesting that several epigenetic mechanisms could coordinately control adult stem cell gene expression programs during organismal aging.…”

CD98hc (SLC3A2) regulation of skin homeostasis wanes with age

“…We now clearly demonstrate a crucial role for CD98hc in maintaining basal keratinocyte functions throughout the epidermis, including IFE and HF, via its ability to mediate integrin signaling. Because most of the human malignancies arise in actively self-renovating sites of epithelial tissues (Sen et al, 2010), integrin signaling is thought to play an important role in formation and maintenance of epithelial cancers (White et al, 2004;Kass et al, 2007). Considering the physiological role of CD98hc in mammalian epithelial tissue formation and homeostasis, and the fact that enhanced expression of CD98hc epithelial neoplasias is indicative of malignant evolution (Cantor and Ginsberg, 2012), it could be hypothesized that novel studies on such a multifunctional protein would pave the way to new discoveries.…”

Smad3 regulates E-cadherin via miRNA-200 pathway

“…To test whether the downregulation of miR-200 family members in SNU484-LPCX cells resulted from miR-200 promoter hypermethylation, we treated SNU484-LPCX cells with 5-aza-2 0 -deoxycytidine. 5-aza-2 0 -deoxycytidine is an irreversible inhibitor of maintenance DNA methyltransferase, which is an enzyme that transfers methyl groups to newly synthesized DNA strands (Sen et al, 2010). Treatment with 5-aza-2 0 -deoxycytidine for 4 days did not increase the expression of miR-200 family members in SNU484-LPCX cells, indicating that promoter hypermethylation is not involved in the downregulation of miR-200 family member expression in SNU484-LPCX cells (Supplementary Figure 7).…”