西亚试剂优势供应上万种化学试剂产品，欢迎各位新老客户咨询、选购！
中国
联系我们
联系方式：400-990-3999 / 邮箱：sales@xiyashiji.com
西亚试剂 —— 品质可靠，值得信赖
1 Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York, United States of America, 2 Department of Medicine, University of Rochester Medical Center, Rochester, New York, United States of America
Transgenerational epigenetic inheritance results from incomplete erasure of parental epigenetic marks during epigenetic reprogramming at fertilization. The significance of this phenomenon, and the mechanism by which it occurs, remains obscure. Here, we show that genetic mutations in Drosophila may cause epigenetic alterations that, when inherited, influence tumor susceptibility of the offspring. We found that many of the mutations that affected tumorigenesis induced by a hyperactive JAK kinase, HopTum-l, also modified the tumor epigenetically, such that the modification persisted even in the offspring that did not inherit the modifier mutation. We analyzed mutations of the transcription repressor Krüppel (Kr), which is one of the hopTum-l enhancers known to affect ftz transcription. We demonstrate that the Kr mutation causes increased DNA methylation in the ftz promoter region, and that the aberrant ftz transcription and promoter methylation are both transgenerationally heritable if HopTum-l is present in the oocyte. These results suggest that genetic mutations may alter epigenetic markings in the form of DNA methylation, which are normally erased early in the next generation, and that JAK overactivation disrupts epigenetic reprogramming and allows inheritance of epimutations that influence tumorigenesis in future generations.
Figure 1.Epigenetic Enhancement of hopTum-l Tumorigenicity by Kr1 or TSA Treatment Requires Maternal hopTum-l
(A) Representative F1 progeny adult flies of indicated genotypes with blood tumors (black masses; arrows) in the abdomen are shown. The parents of these flies were hopTum-l/+ females and wild type males (left), or hopTum-l/+ females and Kr1/CyO males (center and right).
(B–D) The tumor indices of progeny flies (genotypes are indicated in bottom right) are shown as mean and standard deviation of at least three independent crosses. “Control cross F1” were from hopTum-l/+ crossed to wild type. Parental genotypes are indicated on the top. FM7 and CyO are marked balancer chromosomes for the X and second chromosomes carrying a wild-type copy of the hop and Kr genes, respectively. Note that when hopTum-l was inherited from the mother (B, D), but not from the father (C), Kr1 epigenetically enhanced hopTum-l tumorigenicity.
(E) Total protein extracts from adult flies raised on food containing 4.5 μM TSA were subjected to SDS-PAGE and blotted with anti-acetyl-H3. The membrane was stripped and reblotted with anti-H3 (full-length gel image is shown in Figure S1). Quantification of three independent blots is shown to the right.
(F) Tumor indices of F1 progeny from wild-type flies treated or untreated (control) with TSA and hopTum-l/+ females or males as shown. The F1 were raised in the absence of TSA. Tumors were counted in F1 that inherited hopTum-l. Note the parent-of-origin differential effects on the tumorigenesis of F1 flies. Three independent crosses with >200 progeny from each cross were counted. *, p < 0.01; **, p < 0.001, Student's t-test.
