Evidence for Transgenerational Transmission of Epigenetic Tumor Susceptibility in Drosophila

Abstract

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 phenotype 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.

Report of the National Heart, Lung, and Blood Institute Working Group on Epigenetics and Hypertension

“…In many organisms, some epigenetic changes are not erased during gametogenesis and can affect the phenotype and health not only of immediate offspring, but also of future generations through transgenerational effects 27,28,29,30,40,41,42,43,44,45,46,47,48 . Several studies in rodents and other species have revealed remarkable evidence for heritable epigenetic changes where the phenotypic effects of environmental exposure and genetic variants can be transmitted epigenetically across multiple generations.…”

Longevity and the long arm of epigenetics: Acquired parental marks influence lifespan across several generations

“…Similarly, when male rodents are fed a high-fat or low-protein diet, their offspring exhibit severe metabolic defects, which are possibly caused by altered DNA methylation of specific metabolic genes [7, 8]. In addition, several other transgenerational phenomena have been reported in various species, such as paramutation in plants and tumor suscepibility in drosophila [9, 10]. In their recent publication, Greer et al [2] extend the transgenerational phenotype to lifespan.…”

Tertiary Epimutations – A Novel Aspect of Epigenetic Transgenerational Inheritance Promoting Genome Instability

“…Since the initial report of the induction of epigenetic transgenerational inheritance of adult-onset disease in F3 generation progeny from an F0 generation gestating female rat exposed to the endocrine disruptor vinclozolin [1], there have been numerous reports of similar effects caused by exposure of fetuses or adults to a variety of different environmental factors (see [2,3] for reviews), as well as reports of epigenetic transgenerational inheritance in numerous additional species [1,4–9]. These environmental factors include various toxicants, including many different endocrine disruptors, nutrition effects including famine, caloric restriction, high fat diets or folate deficiencies, and other stressors such as drought, smoking, alcohol or heat.…”