Evidence for transgenerational transmission of epigenetic tumor susceptibility in Drosophila.
Evidence for transgenerational transmission of epigenetic tumor susceptibility in Drosophila.
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DOI：
10.1371/journal.pgen.0030151
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发表时间：
2007-09
期刊：
影响因子：
4.5
通讯作者：
Li WX
中科院分区：
文献类型：
--
作者：
Xing Y;Shi S;Le L;Lee CA;Silver-Morse L;Li WX
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. It is well known that many genetic mutations in oncogenes or tumor suppressors can cause or greatly increase a person's susceptibility to cancer. It is generally assumed that persons should feel relieved if they have not inherited the particular “cancer-causing” mutation carried by their parents. However, we found that, under certain circumstances, fruit flies carrying tumor suppressor gene mutations can pass the increased tumor risk to all offspring, even those that have not inherited the particular mutation. 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. Normally, these epigenetic alterations are wiped out and reset in the early embryo, but under certain circumstances such alterations can be inherited. Interestingly, we found evidence that a particular oncoprotein, an overactivated form of a cell-signaling molecule called JAK kinase, can counteract the epigenetic resetting program that normally operates in the early embryo. Thus, the failure of epigenetic reprogramming allows the inheritance of parental epigenetic alterations that affect susceptibility to tumors.
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影响因子：
64.5
作者：
CARROLL, SB;SCOTT, MP
通讯作者：
SCOTT, MP
影响因子：
2.7
作者：
WIESCHAUS, E;NUSSLEINVOLHARD, C;KLUDING, H
通讯作者：
KLUDING, H
影响因子：
64.5
作者：
HIROMI, Y;KUROIWA, A;GEHRING, WJ
通讯作者：
GEHRING, WJ
影响因子：
11.4
作者：
Gowher, H;Leismann, O;Jeltsch, A
通讯作者：
Jeltsch, A
影响因子：
64.5
作者：
Hou, XS;Melnick, MB;Perrimon, N
通讯作者：
Perrimon, N