Short communication: Effects of in-ovo injection of endocrine disruptors and methyltransferase inhibitor on quail growth and egg-laying performances.

Early experiences, including prenatal environment, are known to influence a wide variety of mechanisms involved in the phenotype elaboration. We investigated the effect of the addition of endocrine disruptors or of a methyltransferase inhibitor during the embryonic development of quails from different genetic backgrounds (four different quail lines) on their growth and egg-laying performances. Fifty-four pairs of parents per line were used and fertilised eggs from each pair were randomly divided into five groups: a control group without any injection, an injected control group treated by injection into the egg of sesame oil, and three groups treated by injection of Genistein, Bisphenol A or 5-Aza-2'-deoxycytidine. All quails were individually weighed at 8, 21, 36 and 78 days. The age at first egg laid and the number of eggs laid were recorded. These analyses revealed a significant impact of the treatment on growth but no influence on the egg-laying traits. All three molecules significantly affected at least one of the analysed growth traits. In conclusion, we showed that the injection of endocrine disruptors or DNA methyltransferase inhibitor into the egg had significant effects on quail development; these effects were specific to each treatment, but no interaction between line and treatment was observed.

DNA methylation signal has a major role in the response of human breast cancer cells to the microenvironment.

Breast cancer-associated fibroblasts (CAFs) have a crucial role in tumor initiation, metastasis and therapeutic resistance by secreting various growth factors, cytokines, protease and extracellular matrix components. Soluble factors secreted by CAFs are involved in many pathways including inflammation, metabolism, proliferation and epigenetic modulation, suggesting that CAF-dependent reprograming of cancer cells affects a large set of genes. This paracrine signaling has an important role in tumor progression, thus deciphering some of these processes could lead to relevant discoveries with subsequent clinical implications. Here, we investigated the mechanisms underlying the changes in gene expression patterns associated with the cross-talk between breast cancer cells and the stroma. From RNAseq data obtained from breast cancer cell lines grown in presence of CAF-secreted factors, we identified 372 upregulated genes, exhibiting an expression level positively correlated with the stromal content of breast cancer specimens. Furthermore, we observed that gene expression changes were not mediated through significant DNA methylation changes. Nevertheless, CAF-secreted factors but also stromal content of the tumors remarkably activated specific genes characterized by a DNA methylation pattern: hypermethylation at transcription start site and shore regions. Experimental approaches (inhibition of DNA methylation, knockdown of methyl-CpG-binding domain protein 2 and chromatin immunoprecipitation assays) indicated that this set of genes was epigenetically controlled. These data elucidate the importance of epigenetics marks in the cancer cell reprogramming induced by stromal cell and indicated that the interpreters of the DNA methylation signal have a major role in the response of the cancer cells to the microenvironment.

The PLA2R1-JAK2 pathway upregulates ERRα and its mitochondrial program to exert tumor-suppressive action.

Little is known about the biological role of the phospholipase A2 receptor (PLA2R1) transmembrane protein. In recent years, PLA2R1 has been shown to have an important role in regulating tumor-suppressive responses via JAK2 activation, but the underlying mechanisms are largely undeciphered. In this study, we observed that PLA2R1 increases the mitochondrial content, judged by increased levels of numerous mitochondrial proteins, of the mitochondrial structural component cardiolipin, of the mitochondrial DNA content, and of the mitochondrial DNA replication and transcription factor TFAM. This effect of PLA2R1 relies on a transcriptional program controlled by the estrogen-related receptor alpha1 (ERRα) mitochondrial master regulator. Expression of ERRα and of its nucleus-encoded mitochondrial targets is upregulated upon PLA2R1 ectopic expression, and this effect is mediated by JAK2. Conversely, downregulation of PLA2R1 decreases the level of ERRα and of its nucleus-encoded mitochondrial targets. Finally, blocking the ERRα-controlled mitochondrial program largely inhibits the PLA2R1-induced tumor-suppressive response. Together, our data document ERRα and its mitochondrial program as downstream effectors of the PLA2R1-JAK2 pathway leading to oncosuppression.