Widespread changes to DNA methylation and chromatin are well documented in cancer, but the fate of higher-order chromosomal structure remains obscure. Here we integrated topological maps for colon tumors and normal colons with epigenetic, transcriptional, and imaging data to characterize alterations to chromatin loops, topologically associated domains, and large-scale compartments. We found that spatial partitioning of the open and closed genome compartments is profoundly compromised in tumors. This reorganization is accompanied by compartment-specific hypomethylation and chromatin changes. Additionally, we identify a compartment at the interface between the canonical A and B compartments that is reorganized in tumors. Remarkably, similar shifts were evident in non-malignant cells that have accumulated excess divisions. Our analyses suggest that these topological changes repress stemness and invasion programs while inducing anti-tumor immunity genes and may therefore restrain malignant progression. Our findings call into question the conventional view that tumor-associated epigenomic alterations are primarily oncogenic.
Epigenetic aberrations are widespread in cancer, yet the underlying mechanisms and causality remain poorly understood [1][2][3] . A subset of gastrointestinal stromal tumors (GISTs) lack canonical kinase mutations but instead have succinate dehydrogenase (SDH)-deficiency and global DNA hyper-methylation 4,5 . Here we associate this hyper-methylation with changes in genome topology that activate oncogenic programs. To investigate epigenetic alterations systematically, we mapped DNA methylation, CTCF insulators, enhancers, and chromosome topology in KIT-mutant, PDGFRA-mutant, and SDH-deficient GISTs. Although these respective subtypes shared similar enhancer landscapes, we identified hundreds of putative insulators where DNA methylation replaced CTCF binding in SDH-deficient GISTs. We focused on a disrupted insulator that normally partitions a core GIST super-enhancer from the FGF4 oncogene. Recurrent loss of this insulator alters locus topology in SDH-deficient GISTs, allowing aberrant physical interaction between enhancer and oncogene. CRISPR-mediated excision of the corresponding CTCF motifs in an SDH-intact GIST model disrupted the boundary and strongly up-regulated FGF4 expression. We also identified a second recurrent insulator loss event near the KIT oncogene, which is also highly expressed across SDH-deficient GISTs. Finally, we established a patient-derived xenograft (PDX) from an SDH-deficient GIST that faithfully maintains the epigenetics of the parental tumor, including hyper-methylation and insulator defects. This PDX model is highly sensitive to FGF receptor (FGFR) inhibitor, and more so to combined FGFR and KIT inhibition, validating the functional significance of the underlying epigenetic lesions. Our study reveals how epigenetic alterations can drive oncogenic programs in the absence of canonical kinase mutations, with implications for mechanistic targeting of aberrant pathways in cancers.
The leopard moth, Zeuzera pyrina (L.) (Lepidoptera: Cossidae), is a xylophagous species that has become a serious pest in the olive (Olea spp.) orchards in Egypt. Both chemical and biological control have scored poorly against this pest and additional methods are needed. A simple, but efficient UV-light-pheromone sticky trap (“Hegazi model”) was devised for leopard moth mass trapping. Activity of leopard moth and efficiency of pheromone-baited, light, and pheromone and light traps were evaluated. The combination of light and sex pheromone was optimally attractive to leopard moth populations in olive orchards. A comparison between light traps baited with sex pheromone in mass-trapping method and conventional controls (insecticidal and physical removal of larvae) in heavily infested plots was carried out between 2002 and 2005. Leopard moths have long flight period, starting in mid-May and lasting until early November. Females of leopard moths were rarely trapped, but all had eggs. In mass-trapping plot, the seasonal captures and active galleries diminished from one year to the next, which may indicate the effectiveness of the method. From May 2003 to October 2005 greater reduction in total counts of active galleries was observed in mass-trapping plot compared with those recorded in the control field, in which chemical sprays and manual killing were performed. Yield from trees in mass-trapping field was significantly increased in comparison to control trees. The study strongly recommends the use of mass-trapping method instead of pesticides against the leopard moths, not only to control them but also to mass trap and monitor other lepidopterous pests of olive trees.
The internal parasite Microplitis rufiventris Kok. passes through 3 instars but moults 3 times within its host. The last moult occuring just at emergence time. The morphology of the egg and larval stages of the parasite are discussed. At 27~ and a photoperiod of 6 h (6L: 18 D) the endo-developmental cycle of the parasite can summarize as follows : Egg 18-24 h ; instar 1,4 days (fighting phase 48 h ; feeding phase 30-48 h) ; instar 2, 12-18 h and instar 3,3 days. The effect of different photoperiods on the relative speeds of the endo-developmental stages of the parasite at each of 30, 25, 20~ were carefully studied. At the first 2 temperatures, the short photoperiod (6L:I8D) accelerated the development of larval instars, while both of 18L:6D or 0L:24D slowed down the development. Under the latter photoperiods some larvae failed to moult and had emergence problems. The influence of photoperiod is significantly noticeable at 20~ The incubation period of the egg-stage was prolonged significantly at 18L:6D and the development of larval instars was significantly faster and refined at 6L: 18D. The factor(s) inhibiting the development of the egg-stage perhaps differ from those affecting the iarval development. The ventral area of the host mid-gut among malpighian tubes seems to be where the surplus parasite larvae are eliminated by physical attack. A physiologically suppressed parasite larva is able to attack its developed competitor of the same age. Teratocytes ceils perhaps play a part in eliminating the surplus parasite larvae by physiological suppression.
KEY-WORDS :Microplitis rufiventris, (eggs and larvae), Spodoptera 6ttoralis, Photoperiods, superparasitism, development.Microplitis rufiventris Kok. is reported as a solitary internal larval parasite of the cotton leafworm Spodoptera littoralis (Boisd.), the lesser cotton worm S. exigua Hbn. and American bollworm Heliothis armigera Hbn. M. rufiventris has a short life cycle of ca. 14 days during summer months. Its eggs are laid within the 1st four larval instars of the cotton leafworm. Pupation occurs on a leaf or stem of the plant on which the host was feeding. The parasite has been extensively investigated at the biocontrol unit in Alexandria University, Egypt, as a new potential control agent for some noctuid species (Hammad et al
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