Эпигенетическая модуляция транскрипции генов-мишеней арил-гидрокарбонового рецептора человека в трансгенной линии Drosophila melanogaster

Abstract

Aryl hydrocarbon receptor (AHR), is an important ligand-dependent transcription factor, which retained its structural and functional features during evolution. AHR target genes play a key role in detoxification, in the regulation of the development and maintenance of eukaryotic homeostasis. The high conservatism of human AHR allowed us to study its functions in vivo using transgenic Drosophila melanogaster lines with an inducible human AHR gene. It is believed that Drosophila AHR homolog isn't activated by exogenous ligands, so human AHR can be tissue-specific activated in the body of a transgenic fly. This allows us to analyze the transcription level of AHR target genes in various organs and tissues. Unexpectedly we found that exogenous AHR ligands can increase as well as decrease the transcription levels of the AHR target genes, including genes that control proliferation, motility, polarization, and programmed cell death. We hypothesized that the absence of the expected increase in the transcription of some AHR target genes was caused by its epigenetic silencing. This hypothesis was confirmed in the experiments using histone lysine-N-methyltransferase inhibitors and with Drosophila null mutation of the methyltransferase Pc gene. As a result a new epigenetic mechanism of modulation of human aryl hydrocarbon receptor target genes transcription was discovered. Since exogenous AHR ligands and small molecule inhibitors of epigenetic modifiers are often used as pharmaceutical anticancer drugs, our findings may have significant implications in designing new combinations of therapeutic treatments for oncological diseases.