Dnmt3a and Dnmt3b Associate with Enhancers to Regulate Human Epidermal Stem Cell Homeostasis

Abstract

The DNA methyltransferase Dnmt3a suppresses tumorigenesis in models of leukemia and lung cancer. Conversely, deregulation of Dnmt3b is thought to generally promote tumorigenesis. However, the role of Dnmt3a and Dnmt3b in many types of cancer remains undefined. Here, we show that Dnmt3a and Dnmt3b are dispensable for homeostasis of the murine epidermis. However, loss of Dnmt3a-but not Dnmt3b-increases the number of carcinogen-induced squamous tumors, without affecting tumor progression. Only upon combined deletion of Dnmt3a and Dnmt3b, squamous carcinomas become more aggressive and metastatic. Mechanistically, Dnmt3a promotes the expression of epidermal differentiation genes by interacting with their enhancers and inhibits the expression of lipid metabolism genes, including PPAR-g, by directly methylating their promoters. Importantly, inhibition of PPAR-g partially prevents the increase in tumorigenesis upon deletion of Dnmt3a. Altogether, we demonstrate that Dnmt3a and Dnmt3b protect the epidermis from tumorigenesis and that squamous carcinomas are sensitive to inhibition of PPAR-g.

A genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells

“…8a). Underscoring these findings, we also detected YAP and WBP2 among a set of genes that are actively transcribed from human epidermal SC-specific enhancers (Supplementary Data 11 and 12)4647.…”

Diverse interventions that extend mouse lifespan suppress shared age-associated epigenetic changes at critical gene regulatory regions

“…Losses of methylation at enhancers are only weakly linked to changes in expression of linked genes, and some genes increase and others decrease in expression. Recent studies suggested that DNA methylation of enhancers is required for their functional integrity [48, 59]. So, while age-associated loss of methylation at enhancers in these moderately old mice (22 months old) is only modestly linked to changes in gene expression, it is conceivable that this methylation loss is a precursor to more dramatic changes in methylation and expression in very old mice or perhaps after tissue stress.…”

The contributions of cancer cell metabolism to metastasis

“…DNA methylation also occurs at actively transcribed gene bodies and at active enhancers (Baubec et al, 2015; Charlet et al, 2016; Dhayalan et al, 2010; Rinaldi et al, 2016). DNMTs are responsible for catalysing the transfer of a methyl group to DNA.…”

“…Finally, the intimate interplay between metabolism and epigenetic mechanisms in cancer opens the possibility of targeting both to obtain synergistic effects (Dawson and Kouzarides, 2012; Rinaldi et al, 2016). The recent development of epigenetic inhibitors, which are already being tested in clinical trials, offers hope in this direction (Avgustinova and Benitah, 2016; Tough et al, 2014).…”