Many chemotherapy regiments are successfully used to treat breast cancer; however, often breast cancer cells develop drug resistance that usually leads to a relapse and worsening of prognosis. We have shown recently that epigenetic changes such as DNA methylation and histone modifications play an important role in breast cancer cell resistance to chemotherapeutic agents.

Epigenetic states and certain environmental responses in mammals and seed plants can persist in the next sexual generation. These transgenerational effects have potential adaptative significance as well as medical and agronomic ramifications. Recent evidence suggests that some abiotic and biotic stress responses of plants are transgenerational. For example, viral infection of tobacco plants and exposure of Arabidopsis thaliana plants to UVC and flagellin can induce transgenerational increases in homologous recombination frequency (HRF). Here we show that exposure of Arabidopsis plants to stresses, including salt, UVC, cold, heat and flood, resulted in a higher HRF, increased global genome methylation, and higher tolerance to stress in the untreated progeny. This transgenerational effect did not, however, persist in successive generations. Treatment of the progeny of stressed plants with 5-azacytidine was shown to decrease global genomic methylation and enhance stress tolerance. Dicer-like (DCL) 2 and DCL3 encode Dicer activities important for small RNA-dependent gene silencing. Stress-induced HRF and DNA methylation were impaired in dcl2 and dcl3 deficiency mutants, while in dcl2 mutants, only stress-induced stress tolerance was impaired. Our results are consistent with the hypothesis that stress-induced transgenerational responses in Arabidopsis depend on altered DNA methylation and smRNA silencing pathways.

The gestational state is a period of particular vulnerability to diseases that affect maternal and fetal health. Stress during gestation may represent a powerful influence on maternal mental health and offspring brain plasticity and development. Here we show that the fetal transcriptome, through microRNA (miRNA) regulation, responds to prenatal stress in association with epigenetic signatures of psychiatric and neurological diseases. Pregnant Long-Evans rats were assigned to stress from gestational days 12 to 18 while others served as handled controls. Gestational stress in the dam disrupted parturient maternal behaviour and was accompanied by characteristic brain miRNA profiles in the mother and her offspring, and altered transcriptomic brain profiles in the offspring. In the offspring brains, prenatal stress upregulated miR-103, which is involved in brain pathologies, and downregulated its potential gene target Ptplb. Prenatal stress downregulated miR-145, a marker of multiple sclerosis in humans. Prenatal stress also upregulated miR-323 and miR-98, which may alter inflammatory responses in the brain. Furthermore, prenatal stress upregulated miR-219, which targets the gene Dazap1. Both miR-219 and Dazap1 are putative markers of schizophrenia and bipolar affective disorder in humans. Offspring transcriptomic changes included genes related to development, axonal guidance and neuropathology. These findings indicate that prenatal stress modifies epigenetic signatures linked to disease during critical periods of fetal brain development. These observations provide a new mechanistic association between environmental and genetic risk factors in psychiatric and neurological disease.

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Exposure of animal body parts to ionizing radiation (IR) can lead to molecular changes in distant shielded “bystander” tissues and organs. Nevertheless, tissue specificity of bystander responses within the same organism has not been examined in detail. Studies on in vivo bystander effect conducted so far analyzed changes induced by single‐dose exposure. The potential of fractionated irradiation to induce bystander effects in vivo has never been studied. We analyzed changes in global DNA methylation and microRNAome in skin and spleen of animals subjected to single‐dose (acute or fractionated) whole‐body or cranial exposure to 0.5 Gy of X‐rays. We found that IR‐induced DNA methylation changes in bystander spleen and skin were distinct. Acute radiation exposure resulted in a significant loss of global DNA methylation in the exposed and bystander spleen 6 hr, 96 hr, and 14 days after irradiation. Fractionated irradiation led to hypomethylation in bystander spleen 6 hr after whole‐body exposure, and 6 hr, 96 hr, and 14 days after cranial irradiation. Contrarily, changes in the skin of the same animals were seen only 6 hr after acute whole‐body and head exposure. DNA hypomethylation observed in spleen was paralleled by a reduction of methyl‐binding protein MeCP2 expression. Irradiation also induced tissue‐specific microRNAome alterations in skin and spleen. For the first time, we have shown that IR‐induced epigenetic bystander effects that occur in the same organism are triggered by both acute and fractionated exposure and are very distinct in different bystander organs. Future studies are clearly needed to address organismal and carcinogenic repercussions of those changes. Environ. Mol. Mutagen., 2009. © 2008 Wiley‐Liss, Inc.