While the genomic binding of MYC protein correlates with active epigenetic marks on chromatin, it remains largely unclear how major epigenetic mechanisms functionally impact the tumorigenic potential of MYC. Here we showed that compared to the catalytic subunits, the core subunits, including DPY30, of the major H3K4 methyltransferase complexes were frequently amplified in human cancers, and selectively upregulated in Burkitt lymphoma. We showed that DPY30 promoted expression of endogenous MYC, and was also functionally important for efficient binding of MYC to its genomic targets by regulating chromatin accessibility. Dpy30 heterozygosity did not affect normal animal physiology including life span, but significantly suppressed Myc-driven lymphomagenesis, as cells failed to combat oncogene-triggered apoptosis due to insufficient epigenetic modulation and expression of a subset of anti-apoptotic genes. Dpy30 reduction also greatly impeded MYC-dependent cellular transformation without affecting normal cell growth. These results suggest that MYC hijacks a major epigenetic pathway — H3K4 methylation — to facilitate its molecular activity in target binding and to coordinate its oncogenic program for efficient tumorigenesis, meanwhile creating “epigenetic vulnerability.” DPY30 and the H3K4 methylation pathway are thus potential epigenetic targets for treating certain MYC-driven cancers.
Zhenhua Yang, Kushani Shah, Theodore Busby, Keith Giles, Alireza Khodadadi-Jamayran, Wei Li, Hao Jiang
Neuronatin (Nnat) is an imprinted gene implicated in human obesity and widely expressed in neuroendocrine and metabolic tissues in a hormone and nutrient-sensitive manner. However, its molecular and cellular functions and precise role in organismal physiology remain only partly defined. Here we demonstrate that mice lacking Nnat globally or specifically in β cells display impaired glucose-stimulated insulin secretion leading to defective glucose handling under conditions of nutrient-excess. In contrast, we report no evidence for any feeding or body weight phenotypes in global Nnat null mice. At the molecular level neuronatin augments insulin signal peptide cleavage by binding to the signal peptidase complex and facilitates translocation of the nascent preprohormone. Loss of neuronatin expression in β cells therefore reduces insulin content and blunts glucose-stimulated insulin secretion. Nnat expression, in turn, is glucose-regulated. This mechanism therefore represents a novel site of nutrient-sensitive control of β cell function and whole animal glucose homeostasis. These data also suggest a potential wider role for Nnat in the regulation of metabolism through the modulation of peptide processing events.
Steven J. Millership, Gabriela da Silva Xavier, Agharul I. Choudhury, Sergio Bertazzo, Pauline Chabosseau, Silvia M.A. Pedroni, Elaine E. Irvine, Alex Montoya, Peter Faull, William R. Taylor, Julie Kerr-Conte, Francois Pattou, Jorge Ferrer, Mark Christian, Rosalind M. John, Mathieu Latreille, Ming Liu, Guy A. Rutter, James Scott, Dominic J. Withers
In type 1 diabetes, cytotoxic CD8 T cells with specificity for β-cell autoantigens are found in the pancreatic islets where they are implicated in the destruction of insulin-secreting β cells. In contrast, the disease relevance of β-cell-reactive CD8 T cells that are detectable in the circulation, and their relationship to β-cell function, are not known. Here, we tracked multiple, circulating β-cell-reactive CD8 T cell subsets and measured β-cell function longitudinally for two years, starting immediately after diagnosis of type 1 diabetes. We found that change in β-cell-specific effector memory CD8 T cells expressing CD57 was positively correlated with C-peptide change in subjects below 12 years of age. Autoreactive CD57+ effector memory CD8 T cells bore the signature of enhanced effector function (higher expression of granzyme B, killer specific protein 37 and CD16, and reduced expression of CD28) compared with their CD57-negative counterparts, and network association modelling indicated that the dynamics of β-cell-reactive CD57+ effector memory CD8 T cell subsets were strongly linked. Thus, coordinated changes in circulating β-cell-specific CD8 T cells within the CD57+ effector memory subset calibrate to functional insulin reserve in type 1 diabetes, providing a tool for immune monitoring and a mechanism-based target for immunotherapy.
Lorraine Yeo, Alyssa Woodwyk, Sanjana Sood, Anna Lorenc, Martin Eichmann, Irma Pujol-Autonell, Rossella Melchiotti, Ania Skowera, Efthymios Fidanis, Garry M. Dolton, Katie Tungatt, Andrew K. Sewell, Susanne Heck, Alka Saxena, Craig A. Beam, Mark Peakman
Skeletal muscle has emerged as a critical, disease-relevant target tissue in spinal and bulbar muscular atrophy, a degenerative disorder of the neuromuscular system caused by a CAG/polyglutamine (polyQ) expansion in the androgen receptor (AR) gene. Here, we used RNA-Seq to identify pathways that are disrupted in diseased muscle using AR113Q knock-in mice. This analysis unexpectedly identified significantly diminished expression of numerous ubiquitin-proteasome pathway genes in AR113Q muscle, encoding approximately 30% of proteasome subunits and 20% of E2 ubiquitin conjugases. These changes were age-, hormone- and glutamine length-dependent and arose due to a toxic gain-of-function conferred by the mutation. Moreover, altered gene expression was associated with decreased level of the proteasome transcription factor NRF1 and its activator DDI2 and resulted in diminished proteasome activity. Ubiquitinated ADRM1 was detected in AR113Q muscle, indicating the occurrence of stalled proteasomes in mutant mice. Finally, diminished expression of Drosophila orthologues of NRF1 or ADRM1 promoted the accumulation of polyQ AR protein and increased toxicity. Collectively, these data indicate that AR113Q muscle develops progressive proteasome dysfunction that leads to the impairment of quality control and the accumulation of polyQ AR protein, key features that contribute to the age-dependent onset and progression of this disorder.
Samir R. Nath, Zhigang Yu, Theresa A. Gipson, Gregory B. Marsh, Eriko Yoshidome, Diane M. Robins, Sokol V. Todi, David E. Housman, Andrew P. Lieberman
The tumor-suppressive role of trefoil factor family (TFF) members has been suggested in gastric carcinogenesis, but their significance and mechanisms in other digestive diseases remain elusive. To clarify the role of TFF1 in pancreatic carcinogenesis, we performed immunohistochemistry on human samples, transfected siRNA against TFF1 into pancreatic cancer cell lines, and employed mouse models in which PanIN development and loss of TFF1 occurs simultaneously. In human samples, the expression of TFF1 was specifically observed in pancreatic intraepithelial neoplasm (PanIN) but was frequently lost in the invasive component of pancreatic ductal adenocarcinoma (PDAC). When the expression of TFF1 was suppressed in vitro, pancreatic cancer cell lines showed enhanced invasive ability and features of epithelial-mesenchymal transition (EMT), including upregulated Snail expression. TFF1 expression was also observed in PanIN lesions of Pdx-1 Cre; LSL-KRASG12D (KC) mice, a model of pancreatic cancer, and loss of TFF1 in these mice resulted in the expansion of PanIN lesions, an EMT phenotype in PanIN cells, and an accumulation of cancer-associated fibroblasts (CAFs), eventually resulting in the development of invasive adenocarcinoma. This study indicates that the acquisition of TFF1 expression is an early event in pancreatic carcinogenesis and that TFF1 might act as a tumor suppressor to prevent EMT and the invasive transformation of PanIN.
Junpei Yamaguchi, Yukihiro Yokoyama, Toshio Kokuryo, Tomoki Ebata, Atsushi Enomoto, Masato Nagino
Enterotoxigenic Escherichia coli (ETEC) infections are highly prevalent in developing countries where clinical presentations range from asymptomatic colonization to severe cholera-like illness. The molecular basis for these varied presentations, that may involve strain-specific virulence features as well as host factors, have not been elucidated. We demonstrate that when challenged with ETEC strain H10407, originally isolated from a case of cholera-like illness, blood group A human volunteers developed severe diarrhea more frequently than individuals from other blood groups. Interestingly, a diverse population of ETEC strains, including H10407, secrete a novel adhesin molecule, EtpA. As many bacterial adhesins also agglutinate red blood cells, we combined the use of glycan arrays, biolayer inferometry, and non-canonical amino acid labeling with hemagglutination studies to demonstrate that EtpA is a dominant ETEC blood group A specific lectin/hemagglutinin. Importantly, we also show that EtpA interacts specifically with glycans expressed on intestinal epithelial cells from blood group A individuals, and that EtpA-mediated bacterial-host interactions accelerate bacterial adhesion and the effective delivery both heat-labile and heat-stable toxins of ETEC. Collectively, these data provide additional insight into the complex molecular basis of severe ETEC diarrheal illness that may inform rational design of vaccines to protect those at highest risk.
Pardeep Kumar, F. Matthew Kuhlmann, Subhra Chakroborty, A. Louis Bourgeois, Jennifer Foulke-Abel, Brunda Tumala, Tim J. Vickers, David A. Sack, Barbara DeNearing, Clayton D. Harro, W. Shea Wright, Jeffrey C. Gildersleeve, Matthew A. Ciorba, Srikanth Santhanam, Chad K. Porter, Ramiro L. Gutierrez, Michael G. Prouty, Mark S. Riddle, Alexander Polino, Alaullah Sheikh, Mark Donowitz, James M. Fleckenstein
Cancer progression is associated with alterations of intra- and extramedullary hematopoiesis to support a systemic tumor-promoting myeloid response. However, the functional specialty, mechanism, and clinical relevance of extramedullary hematopoiesis (EMH) remain unclear. Here we showed that the heightened splenic myelopoiesis in tumor-bearing hosts was not only characterized by the accumulation of myeloid precursors, but also associated with profound functional alterations of splenic early hematopoietic stem/progenitor cells (HSPCs). With the distinct capability to produce and respond to granulocyte-macrophage colony-stimulating factor (GM-CSF), these splenic HSPCs were “primed” and committed to generating immunosuppressive myeloid cells. Mechanistically, the CCL2-CCR2 axis-dependent recruitment and the subsequent local education by the splenic stroma were critical for eliciting this splenic HSPC response. Selective abrogation of this splenic EMH was sufficient to synergistically enhance the therapeutic efficacy of immune checkpoint blockade. Clinically, patients with different types of solid tumors exhibited increased splenic HSPC levels associated with poor survival. These findings reveal a unique and important role of splenic hematopoiesis in the tumor-associated myelopoiesis.
Chong Wu, Huiheng Ning, Mingyu Liu, Jie Lin, Shufeng Luo, Wenjie Zhu, Jing Xu, Wen-Chao Wu, Jing Liang, Chun-Kui Shao, Jiaqi Ren, Bin Wei, Jun Cui, Min-Shan Chen, Limin Zheng
Broad-spectrum antibiotics are widely used in patients on intensive care units (ICU), many of which develop hospital-acquired infections with Pseudomonas aeruginosa. Although preceding antimicrobial therapy is known as a major risk factor for P. aeruginosa-induced pneumonia, the underlying mechanisms remain incompletely understood. Here we demonstrate that depletion of the resident microbiota by broad-spectrum antibiotic treatment inhibited TLR-dependent production of a proliferation inducing ligand (APRIL), resulting in a secondary IgA deficiency in the lung in mice and human ICU patients. Microbiota-dependent local IgA contributed to early antibacterial defense against P. aeruginosa. Consequently, Pseudomonas-binding IgA purified from lamina propria culture or IgA hybridomas enhanced resistance of antibiotic-treated mice to P. aeruginosa infection after transnasal substitution. Our study provides a mechanistic explanation for the well-documented risk of P. aeruginosa infection following antimicrobial therapy, and we propose local administration of IgA as a novel prophylactic strategy.
Oliver H. Robak, Markus M. Heimesaat, Andrey A. Kruglov, Sandra Prepens, Justus Ninnemann, Birgitt Gutbier, Katrin Reppe, Hubertus Hochrein, Mark Suter, Carsten J. Kirschning, Veena Marathe, Jan Buer, Mathias W. Hornef, Markus Schnare, Pascal Schneider, Martin Witzenrath, Stefan Bereswill, Ulrich Steinhoff, Norbert Suttorp, Leif E. Sander, Catherine Chaput, Bastian Opitz
Tumor angiogenesis occurs through regulation of genes that orchestrate endothelial sprouting and vessel maturation, including deposition of a vessel-associated extracellular matrix. CD93 is a transmembrane receptor that is up-regulated in tumor vessels in many cancers, including high-grade glioma. Here, we demonstrate that CD93 regulates integrin-β1-signaling and organization of fibronectin fibrillogenesis during tumor vascularization. In endothelial cells and mouse retina, CD93 was found to be expressed in endothelial filopodia and to promote filopodia formation. The CD93 localization to endothelial filopodia was stabilized by interaction with multimerin-2 (MMRN2), which inhibited its proteolytical cleavage. The CD93-MMRN2 complex was required for activation of integrin-β1, phosphorylation of focal adhesion kinase (FAK) and fibronectin fibrillogenesis in endothelial cells. Consequently, tumor vessels in gliomas implanted orthotopically in CD93-deficient mice showed diminished activation of integrin-β1 and lacked organization of fibronectin into fibrillar structures. These findings demonstrate a key role of CD93 in vascular maturation and organization of the extracellular matrix in tumors, identifying it as a potential target for therapy.
Roberta Lugano, Kalyani Vemuri, Di Yu, Michael Bergqvist, Anja Smits, Magnus Essand, Staffan Johansson, Elisabetta Dejana, Anna Dimberg
Tumor Necrosis Factor (TNF) is an important mediator in numerous inflammatory diseases, e.g., in inflammatory bowel diseases (IBD). In IBD, acute increases in TNF production can lead to disease flares. Glucocorticoids (GCs), which are steroids that bind and activate the glucocorticoid receptor (GR), are able to protect animals and humans against acute TNF-induced inflammatory symptoms. Mice with a poor transcriptional response of GR-dimer-dependent target genes were studied in a model of TNF-induced lethal inflammation. In contrast to the GRwt/wt mice, these GRdim/dim mice displayed a significant increase in TNF sensitivity and a lack of protection by the GC dexamethasone (DEX). Unchallenged GRdim/dim mice had a strong interferon-stimulated gene (ISG) signature, along with STAT1 upregulation and phosphorylation. This ISG signature was gut specific and, based on our studies with antibiotics, depended on the gut microbiota. GR dimers directly bound to short DNA sequences in the STAT1 promoter known as inverted repeat negative GRE (IR-nGRE) elements. Poor control of STAT1 in GRdim/dim mice led to failure to repress ISG genes resulting in excessive necroptosis induction by TNF. Our findings support a critical interplay between gut microbiota, interferons, necroptosis and GR in both the basal response to acute inflammatory challenges and in the pharmacological intervention by GCs.
Marlies Ballegeer, Kelly Van Looveren, Steven Timmermans, Melanie Eggermont, Sofie Vandevyver, Fabien Thery, Karen Dendoncker, Jolien Souffriau, Jolien Vandewalle, Lise Van Wyngene, Riet De Rycke, Nozomi Takahashi, Peter Vandenabeele, Jan Tuckermann, Holger M. Reichardt, Francis Impens, Rudi Beyaert, Karolien De Bosscher, Roosmarijn E. Vandenbroucke, Claude Libert
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