The role of DNA methylation and of the maintenance DNA methyltransferase Dnmt1 in the epigenetic regulation of developmental stage- and cell lineage-specific gene expression in vivo is uncertain. This is addressed here through the generation of mice in which Dnmt1 was inactivated by Cre/loxP-mediated deletion at sequential stages of T cell development. Deletion of Dnmt1 in early double-negative thymocytes led to impaired survival of TCRalphabeta(+) cells and the generation of atypical CD8(+)TCRgammadelta(+) cells. Deletion of Dnmt1 in double-positive thymocytes impaired activation-induced proliferation but differentially enhanced cytokine mRNA expression by naive peripheral T cells. We conclude that Dnmt1 and DNA methylation are required for the proper expression of certain genes that define fate and determine function in T cells.
Tumor metastasis is a multistep process by which tumor cells disseminate from their primary site and form secondary tumors at a distant site. Metastasis occurs through a series of steps: local invasion, intravasation, transport, extravasation, and colonization. A developmental program termed epithelial-mesenchymal transition (EMT) has been shown to play a critical role in promoting metastasis in epithelium-derived carcinoma. Recent experimental and clinical studies have improved our knowledge of this dynamic program and implicated EMT and its reverse program, mesenchymal-epithelial transition (MET), in the metastatic process. Here, we review the functional requirement of EMT and/or MET during the individual steps of tumor metastasis and discuss the potential of targeting this program when treating metastatic diseases.Epithelial and mesenchymal cell types have long been recognized by their unique cell morphology and organization in tissues. Epithelial cells form polarized sheets or layers of cells that are connected laterally via several types of cellular junctions, including adherens junctions, desmosomes, and tight junctions. In addition, epithelial cells anchor themselves to the underlying basement membrane via hemidesmosomes to maintain apical-basal polarity. Both desmosomes and hemidesmosomes further connect with the epithelial-specific cytokeratin intermediate filaments. In contrast, mesenchymal cells embed themselves inside the extracellular matrix (ECM) and rarely establish tight contact with neighboring cells. During specific embryonic morphogenesis processes such as mesoderm formation and neural crest development, epithelial cells can exhibit enormous plasticity and transit into a mesenchymal state by activating the epithelial-mesenchymal transition (EMT) program. After EMT, these cells lose their epithelial junctions and switch to producing vimentin filaments. The functional hallmark of the EMT program is to allow stationary epithelial cells to gain the ability to migrate and invade during developmental morphogenesis (Boyer and Thiery 1993;Hay 1995).Although epithelial cells convert into the mesenchymal state during developmental EMT, entering the EMT program is not necessarily an irreversible commitment, as evident during kidney tubule formation. These epithelial cells can activate a transitory EMT program and then undergo a reverse process called mesenchymal-epithelial transition (MET) to continue their differentiation paths (Thiery et al. 2009;Lim and Thiery 2012). In many instances, the identification of an epithelial versus a mesenchymal state can be relatively fluid, and a partial EMT/MET frequently occurs to fulfill unique developmental tasks. These dynamic EMT/MET events highlight the enormous flexibility of presumably differentiated cells during morphogenesis.In the past decade, an increasing number of studies have provided strong evidence for the reinitiation of the EMT developmental program in carcinoma progression and metastasis. This EMT program in tumor metastasis possesses many morpholog...
Summary Epithelial-Mesenchymal Transition (EMT) is implicated in converting stationary epithelial tumor cells into motile mesenchymal cells during metastasis. However, the involvement of EMT in metastasis is still controversial due to the lack of a mesenchymal phenotype in human carcinoma metastases. Using a spontaneous squamous cell carcinoma mouse model, we show that activation of the EMT-inducing transcription factor Twist1 is sufficient to promote carcinoma cells to undergo EMT and disseminate into blood circulation. Importantly, in distant sites, turning off Twist1 to allow reversion of EMT is essential for disseminated tumor cells to proliferate and form metastases. Our study demonstrates in vivo the requirement of “reversible EMT” in tumor metastasis and may resolve the controversy on the importance of EMT in carcinoma metastasis.
Matrix stiffness potently regulates cellular behavior in various biological contexts. In breast tumours, the presence of dense clusters of collagen fibrils indicates increased matrix stiffness and correlates with poor survival. It is unclear how mechanical inputs are transduced into transcriptional outputs to drive tumour progression. Here we report that TWIST1 is an essential mechano-mediator that promotes epithelial-mesenchymal transition (EMT) in response to increasing matrix stiffness. High matrix stiffness promotes nuclear translocation of TWIST1 by releasing TWIST1 from its cytoplasmic binding partner G3BP2. Loss of G3BP2 leads to constitutive TWIST1 nuclear localization and synergizes with increasing matrix stiffness to induce EMT and promote tumour invasion and metastasis. In human breast tumours, collagen fiber alignment, a marker of increasing matrix stiffness, and reduced expression of G3BP2 together predict poor survival. Our findings reveal a TWIST1-G3BP2 mechanotransduction pathway that responds to biomechanical signals from the tumour microenvironment to drive EMT, invasion, and metastasis.
Lipopolysaccharide (LPS) is the principal proinflammatory component of the Gram-negative bacterial envelope and is recognized by the Toll-like receptor 4 (TLR4)-MD-2 receptor complex. Bacteria can alter the acylation state of their LPS in response to environmental changes. One opportunistic bacterium, Pseudomonas aeruginosa, synthesizes more highly acylated (hexa-acylated) LPS structures during adaptation to the cystic fibrosis airway. Here we show that human, but not murine, TLR4-MD-2 recognizes this adaptation and transmits robust proinflammatory signals in response to hexa-acylated but not penta-acylated LPS from P. aeruginosa. Whereas responses to lipidIVA and taxol are dependent on murine MD-2, discrimination of P. aeruginosa LPS structures is mediated by an 82-amino-acid region of human TLR4 that is hypervariable across species. Thus, in contrast to mice, humans use TLR4 to recognize a molecular signature of bacterial-host adaptation to modulate the innate immune response.
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