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.
Highlights
Epigenetic regulation of gene expression refers to repression or activation of gene expression via covalent modifications of DNA or histones, such as methylation or acetylation, without changing the DNA sequence of the gene [1,2,3]
Genomic imprinting, where clusters of genes or whole chromosomes are preferentially inactivated depending on their parental origin [8,9], can be considered an exception to epigenetic reprogramming, because in this case parental epigenetic markings are retained in the zygote
A likely scenario is that many genetic mutations can lead to epigenetic alterations, that is, changes in the chemical modifications of DNA or the proteins that bind to DNA in the chromosomes, and these changes can have global effects on cell function
Summary
Epigenetic regulation of gene expression refers to repression or activation of gene expression via covalent modifications of DNA or histones, such as methylation or acetylation, without changing the DNA sequence of the gene [1,2,3]. Genomic imprinting, where clusters of genes or whole chromosomes are preferentially inactivated depending on their parental origin [8,9], can be considered an exception to epigenetic reprogramming, because in this case parental epigenetic markings are retained in the zygote. Loss of imprinting has been shown to increase the likelihood that cancer will develop [10,11,12]. Human diseases, such as Prader-Willi and Angelman syndromes [13] and hereditary nonpolyposis colorectal cancer [14], are associated with germline inheritance of epimutations. Though transgenerational epigenetic inheritance has been documented for a variety of eukaryotic organisms ranging from plants to humans [15], the precise mechanisms that regulate epigenetic marking and erasure, as well as those that protect certain epigenetic marks from being reset, are not clear
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