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, Hop Tum-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 hop Tum-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 Hop Tum-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.

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.

The canonical JAK-STAT signaling pathway transmits signals from the cell membrane to the nucleus, to regulate transcription of particular genes involved in development and many other physiological processes. It has been shown in Drosophila that JAK and STAT also function in a non-canonical mode, to regulate heterochromatin. This review discusses the non-canonical functioning of JAK and STAT, and its effects on biological processes. Decreased levels of activated JAK and increased levels of unphosphorylated STAT generate higher levels of heterochromatin. These higher heterochromatin levels result in suppression of hematopoietic tumor-like masses, increased resistance to DNA damage, and longer lifespan.

During embryonic development in Drosophila, rodents, and other organisms, primordial germ cells (PGCs) migrate from their points of origin to the nascent gonads, where they give rise to germ line stem cells. Receptor tyrosine kinase (RTK) activity is required for normal migration of primordial germ cells in both Drosophila and rodents. In this chapter, we discuss in vivo as well as in vitro methods which have been used to elucidate the role of the RTK Torso in Drosophila germ cell migration. Included are protocols for embryo collection, fixation, and immunostaining; the dominant female sterile technique; in vitro culture and observation of PGCs; pole cell transplantation; and labeling of pole cells for in vivo observation.

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