Aryl hydrocarbon receptor (AHR) is the key transcription factor that controls animal development and various adaptive processes. The AHR’s target genes are involved in biodegradation of endogenous and exogenous toxins, regulation of immune response, organogenesis, and neurogenesis. Ligand binding is important for the activation of the AHR signaling pathway. Invertebrate AHR homologs are activated by endogenous ligands whereas vertebrate AHR can be activated by both endogenous and exogenous ligands (xenobiotics). Several studies using mammalian cultured cells have demonstrated that transcription of the AHR target genes can be activated by exogenous AHR ligands, but little is known about the effects of AHR in a living organism. Here, we examined the effects of human AHR and its ligands using transgenic Drosophila lines with an inducible human AhR gene. 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. This suggests that AHR activation may affect the expression of gene networks that could be critical for cancer progression and metastasis. Importantly, we found that AHR target genes are also controlled by the enzymes that modify chromatin structure, in particular components of the epigenetic Polycomb Repressive complexes 1 and 2. Since exogenous AHR ligands (alternatively – xenobiotics) 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.

To study the regulatory mechanism of the Aryl hydrocarbon receptor (AHR), target genes of transcription are necessary for understanding the normal developmental and pathological processes. Here, we examined the effects of human AHR ligands on male fecundity. To induce ectopic human AhR gene expression, we used Drosophila melanogaster transformed with human AhR under the control of a yeast UAS promoter element capable of activation in the two-component UAS-GAL4 system. We found that exogenous AHR ligands decrease the number of Drosophila gonadal Tj-positive cells. We also found both an increase and decrease of AHR target gene expression, including in genes that control homeostasis and testis development. This suggests that gonadal AHR activation may affect the expression of gene networks that control sperm production and could be critical for fertility not just in Drosophila but also in humans. Finally, we found that the activation of the expression for some AHR target genes depends on the expression of testis-specific chaperone CG5017 in gonadal cells. Since CG5017 belongs to the nucleosome assembly protein (NAP) family and may participate in epigenetic regulation, we propose that this nucleotropic chaperone is essential to provide the human AHR with access to only the defined set of its target genes during spermatogenesis.

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Остеогенная саркома -агрессивная злокачественная опухоль костной ткани, возникающая в молодом возрасте (10-19 лет) и, как правило, заканчивающаяся фатально. Арил-гидрокарбоновый рецептор человека (Aryl Hydrocarbon Receptor, AHR) -лиганд-зависимый транскрипционный фактор, который связан с детоксикацией ксенобиотиков и канцерогенезом. Известно, что некоторые лиганды AHR входят в состав фармацевтических препаратов, применяемых в онкотерапии. Однако в мировой литературе мало работ, посвященных исследованию последствий их воздействия на клетки остеосаркомы. В данной работе были получены три первичные культуры из биопсийного материала злокачественных опухолей костной ткани остеогенной саркомы человека. Во всех культурах остеосарком было отмечено повышенное содержание белка AHR по сравнению с линиями клеток неопухолевого происхождения. Функциональную активность AHR в клетках остеосарком оценивали по специфичности активации его генов-мишеней после применения известных экзогенных лигандов: индирубина и индол-3-карбинола. В качестве генов-мишеней AHR анализировали гены одного семейства цитохромов: CYP1A1, CYP1A2, CYP1B1. Было показано, что во всех полученных культурах AHR функционально активен, однако профиль активации экспрессии его генов-мишеней в ответ на действие лиганда варьировал.

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