The aryl hydrocarbon receptor (AHR) is a markedly established regulator of a plethora of cellular and molecular processes. Its initial role in the detoxification of xenobiotic compounds has been ...partially overshadowed by its involvement in homeostatic and organ physiology processes. In fact, the discovery of its ability to bind specific target regulatory sequences has allowed for the understanding of how AHR modulates such processes. Thereby, AHR presents functions in transcriptional regulation, chromatin architecture modifications and participation in different key signaling pathways. Interestingly, such fields of influence end up affecting organ and tissue homeostasis, including regenerative response both to endogenous and exogenous stimuli. Therefore, from classical spheres such as canonical transcriptional regulation in embryonic development, cell migration, differentiation or tumor progression to modern approaches in epigenetics, senescence, immune system or microbiome, this review covers all aspects derived from the balance between regulation/deregulation of AHR and its physio-pathological consequences.
•TCDD induces toxicity in SHSY5Y human neuroblastoma cells.•TCDD toxicity in SHSY5Y neuroblastoma cells depends on dioxin concentration and time of incubation.•Transient transfection of a hairpin RNA ...for AhR protects against TCDD neurotoxicity.
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a xenobiotic agent with high persistency that induces neurotoxic effects altering neurodevelopment and behavior. The molecular mechanisms and the signaling pathways involved in TCDD-mediated neurotoxicity, together with the search of its molecular targets in neurons are under intense study. We have previously shown that high nanomolar concentrations of TCDD for incubation times of minutes induce apoptosis in SHSY5Y human neuroblastoma cells by the disruption of calcium homeostasis, affecting membrane structural integrity. In this work, we have analyzed the effect of low nanomolar concentrations of TCDD for incubation times of hours to define the role of aryl hydrocarbon receptor which can be activated at those concentrations. TCDD induces toxicity in SHSY5Y human neuroblastoma cells under these experimental conditions with an EC50 value of approximately 3nM at 24h of incubation time. Transient transfection of a hairpin RNA for AhR protects against TCDD neurotoxicity, suggesting that AhR is mediating the dioxin effect. Altogether, these results support the hypothesis that TCDD toxicity in SHSY5Y neuroblastoma cells depends on dioxin concentration and time of incubation, with a main role of aryl hydrocarbon receptor at low nanomolar TCDD concentrations.
The liver is among the few organs having the ability to self-regenerate in response to a severe damage compromising its functionality. The Aryl hydrocarbon receptor (Ahr) is a transcription factor ...relevant for the detoxification of xenobiotics but also largely important for liver development and homeostasis. Hence, liver cell differentiation is developmentally modulated by Ahr through the controlled expression of pluripotency and stemness-inducing genes. Here, 2/3 partial hepatectomy (PH) was used as a clinically relevant approach to induce liver regeneration in Ahr-expressing (Ahr
) and Ahr-null (Ahr
) mice. Ahr expression and activity were early induced after 2/3 PH to be gradually downmodulated latter during regeneration. Ahr
mice triggered liver regeneration much faster than AhR
animals, although both reached full regeneration at the latest times. At initial stages after PHx, earlier regenerating Ahr
livers had upregulation of cell proliferation markers and increased activation of signalling pathways related to stemness such as Hippo-YAP and Wnt/β-catenin, concomitantly with the induction of pro-inflammatory cytokines TNFa, IL6 and p65. These phenotypes, together with the improved metabolic adaptation of Ahr
mice after PHx and their induced sustained cell proliferation, could likely result from the expansion of undifferentiated stem cells residing in the liver expressing OCT4, SOX2, KLF4 and NANOG. We propose that Ahr needs to be induced early during regeneration to fine-tune liver regrowth to physiological values. Since Ahr deficiency did not result in liver overgrowth, its transient pharmacological inhibition could serve to improve liver regeneration in hepatectomized and transplanted patients and in those exposed to damaging liver toxins and carcinogens.
Cell differentiation is a central process in development and in cancer growth and dissemination. OCT4 (POU5F1) and NANOG are essential for cell stemness and pluripotency; yet, the mechanisms that ...regulate their expression remain largely unknown. Repetitive elements account for almost half of the Human Genome; still, their role in gene regulation is poorly understood. Here, we show that the dioxin receptor (AHR) leads to differentiation of human carcinoma cells through the transcriptional upregulation of Alu retrotransposons, whose RNA transcripts can repress pluripotency genes. Despite the genome-wide presence of Alu elements, we provide evidences that those located at the NANOG and OCT4 promoters bind AHR, are transcribed by RNA polymerase-III and repress NANOG and OCT4 in differentiated cells. OCT4 and NANOG repression likely involves processing of Alu-derived transcripts through the miRNA machinery involving the Microprocessor and RISC. Consistently, stable AHR knockdown led to basal undifferentiation, impaired Alus transcription and blockade of OCT4 and NANOG repression. We suggest that transcripts produced from AHR-regulated Alu retrotransposons may control the expression of stemness genes OCT4 and NANOG during differentiation of carcinoma cells. The control of discrete Alu elements by specific transcription factors may have a dynamic role in genome regulation under physiological and diseased conditions.
Complex genomes utilize insulators and boundary elements to help define spatial and temporal gene expression patterns. We report that a genome-wide B1 SINE (Short Interspersed Nuclear Element) ...retrotransposon (B1-X35S) has potent intrinsic insulator activity in cultured cells and live animals. This insulation is mediated by binding of the transcription factors dioxin receptor (AHR) and SLUG (SNAI2) to consensus elements present in the SINE. Transcription of B1-X35S is required for insulation. While basal insulator activity is maintained by RNA polymerase (Pol) III transcription, AHR-induced insulation involves release of Pol III and engagement of Pol II transcription on the same strand. B1-X35S insulation is also associated with enrichment of heterochromatin marks H3K9me3 and H3K27me3 downstream of B1-X35S, an effect that varies with cell type. B1-X35S binds parylated CTCF and, consistent with a chromatin barrier activity, its positioning between two adjacent genes correlates with their differential expression in mouse tissues. Hence, B1 SINE retrotransposons represent genome-wide insulators activated by transcription factors that respond to developmental, oncogenic, or toxicological stimuli.
Aging impairs organismal homeostasis leading to multiple pathologies. Yet, the mechanisms and molecular intermediates involved are largely unknown. Here, we report that aged aryl hydrocarbon ...receptor-null mice (
) had exacerbated cellular senescence and more liver progenitor cells. Senescence-associated markers β-galactosidase (SA-β-Gal), p16
and p21
and genes encoding senescence-associated secretory phenotype (SASP) factors TNF and IL1 were overexpressed in aged
livers. Chromatin immunoprecipitation showed that AhR binding to those gene promoters repressed their expression, thus adjusting physiological levels in
livers. MCP-2, MMP12 and FGF secreted by senescent cells were overproduced in aged AhR-null livers. Supporting the relationship between senescence and stemness, liver progenitor cells were overrepresented in
mice, probably contributing to increased hepatocarcinoma burden. These AhR roles are not liver-specific since adult and embryonic AhR-null fibroblasts underwent senescence in culture, overexpressing SA-β-Gal, p16
and p21
. Notably, depletion of senescent cells with the senolytic agent navitoclax restored expression of senescent markers in
fibroblasts, whereas senescence induction by palbociclib induced an AhR-null-like phenotype in
fibroblasts. AhR levels were downregulated by senescence in mouse lungs but restored upon depletion of p16
-expressing senescent cells. Thus, AhR restricts age-induced senescence associated to a differentiated phenotype eventually inducing resistance to liver tumorigenesis.
Virtual desktops in cloud scenarios play a significant role in higher education. Nowadays, the idea of moving laboratories to the cloud seems mandatory and it is necessary to maintain students’ ...commitment in this new scenario. This paper aims at two targets, customizing a Virtual Desktop platform for delivering the laboratories of a programming course in a Computer Science Bachelor Degree and empirically apply the technology acceptance model and the system usability scale to a set of students that use it. Results obtained in this paper provide insights about the direct effect between the perceived ease of use, perceived usefulness, and attitude to technology following the technology acceptance model (TAM) as well as a comprehensive analysis of the system usability scale (SUS) of our platform.
•A sensor system for the identification of hydrocarbons and their mixtures based on photonic transducers is proposed.•The transducers are resistant to high temperature, high pressure, and harsh ...working conditions.•Complementary use of interferometric and NIR transducers improves the system sensing performance for oils and fractions.•Dynamic analysis in flow conditions of crude oil mixtures is presented.
Identification of hydrocarbons and crude oils is typically carried out with samples that, taken from natural sources or refineries, must be brought to the laboratory for their analysis with rather sophisticated instruments. Alternatively, “in situ” procedures have been also developed for this purpose. In this work, we propose the use of a series of several sensor systems based on photonic transducers in the form of chips for the identification and classification of crude oils and hydrocarbons through the determination of their refractive index in the visible and absorption in the near infrared regions of the electromagnetic spectrum. Two of the photonic transducers rely on modifications of a Bragg microcavity and they monitor the changes in visible light interference phenomena that occur in response to the variation of the refractive index of oils. The third one, in the form of a dielectric mirror, monitors the near infrared absorption of crude oils and hydrocarbons through the recording of a transflectance spectrum. The capacity of these transducers for crude oil identification is proved by the analysis of a series of oils and distilled fractions that have been properly identified and classified as a function of their density and partition of long hydrocarbon chains. The three photonic transducers are operated with optical fibers and can be used in static and dynamic modes, this latter under conditions that are especially well-suited for “in-situ” analysis of oil streams in real facilities. The proved resistance of the chips to high pressure and temperature conditions supports their suitability to withstand harsh working environments as those existing in extraction wells.
Transcriptional repression of Nanog is an important hallmark of stem cell differentiation. Chromatin modifications have been linked to the epigenetic profile of the Nanog gene, but whether chromatin ...organization actually plays a causal role in Nanog regulation is still unclear. Here, we report that the formation of a chromatin loop in the Nanog locus is concomitant to its transcriptional downregulation during human NTERA-2 cell differentiation. We found that two Alu elements flanking the Nanog gene were bound by the aryl hydrocarbon receptor (AhR) and the insulator protein CTCF during cell differentiation. Such binding altered the profile of repressive histone modifications near Nanog likely leading to gene insulation through the formation of a chromatin loop between the two Alu elements. Using a dCAS9-guided proteomic screening, we found that interaction of the histone methyltransferase PRMT1 and the chromatin assembly factor CHAF1B with the Alu elements flanking Nanog was required for chromatin loop formation and Nanog repression. Therefore, our results uncover a chromatin-driven, retrotransposon-regulated mechanism for the control of Nanog expression during cell differentiation.
Herein, we present the development of supported organic nanofabrics formed by a conformal polymer-like interconnection of small-molecule organic nanowires and nanotrees. These organic nanostructures ...are fabricated by a combination of vacuum and plasma-assisted deposition techniques to generate step by step, single-crystalline organic nanowires forming one-dimensional building blocks, organic nanotrees applied as three-dimensional templates, and the polymer-like shell that produces the final fabric. The complete procedure is carried out at low temperatures and is compatible with an ample variety of substrates (polymers, metal, ceramics; either planar or in the form of meshes) yielding flexible and low solid-fraction three-dimensional nanostructures. The systematic investigation of this progressively complex organic nanomaterial delivers key clues relating their wetting, nonwetting, and anti-icing properties with their specific morphology and outer surface composition. Water contact angles higher than 150° are attainable as a function of the nanofabric shell thickness with outstanding freezing-delay times (FDT) longer than 2 h at −5 °C. The role of the extremely low roughness of the shell surface is settled as a critical feature for such an achievement. In addition, the characteristic interconnected microstructure of the nanofabrics is demonstrated as ideal for the fabrication of slippery liquid-infused porous surfaces (SLIPS). We present the straightforward deposition of the nanofabric on laser patterns and the knowledge of how this approach provides SLIPS with FDTs longer than 5 h at −5 °C and 1 h at −15 °C.
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