Glucocorticoid stimulation induces regionalized gene responses within topologically associating domains.

Transcription-factor binding to cis-regulatory regions regulates the gene expression program of a cell, but occupancy is often a poor predictor of the gene response. Here, we show that glucocorticoid stimulation led to the reorganization of transcriptional coregulators MED1 and BRD4 within topologically associating domains (TADs), resulting in active or repressive gene environments. Indeed, we observed a bias toward the activation or repression of a TAD when their activities were defined by the number of regions gaining and losing MED1 and BRD4 following dexamethasone (Dex) stimulation. Variations in Dex-responsive genes at the RNA levels were consistent with the redistribution of MED1 and BRD4 at the associated cis-regulatory regions. Interestingly, Dex-responsive genes without the differential recruitment of MED1 and BRD4 or binding by the glucocorticoid receptor were found within TADs, which gained or lost MED1 and BRD4, suggesting a role of the surrounding environment in gene regulation. However, the amplitude of the response of Dex-regulated genes was higher when the differential recruitment of the glucocorticoid receptor and transcriptional coregulators was observed, reaffirming the role of transcription factor-driven gene regulation and attributing a lesser role to the TAD environment. These results support a model where a signal-induced transcription factor induces a regionalized effect throughout the TAD, redefining the notion of direct and indirect effects of transcription factors on target genes.

The gut-liver axis: host microbiota interactions shape hepatocarcinogenesis.

Although their etiologies vary, tumors share a common trait: the control of an oncogenic transcriptional program that is regulated by the interaction of the malignant cells with the stromal and immune cells in the tumor microenvironment (TME). The TME shows high phenotypic and functional heterogeneity that may be modulated by interactions with commensal microbes (the microbiota) both systemically and locally. Unlike host cells, the microbiota adapts after environmental perturbations, impacting host-microbe interactions. In the liver, the bidirectional relationship in the gut and its associated microbiota creates an interdependent environment. Therefore, the gut microbiota and its metabolites modulate liver gene expression directly and indirectly, causing an imbalance in the gut-liver axis, which may result in disease, including carcinogenesis.

Mitochondrial-related gene associated to obesity can be modulated by in utero hyperglycemic environment.

We investigated whether mitochondrial-related genes and proteins are modulated by hyperglycemia promoted by gestational diabetes (GDM), thereby increasing neonate obesity predisposition. 19 healthy pregnant women, 16 pregnant women with GDM and their respective neonates were enrolled. Additionally, 19 obese and 19 eutrophic adults were recruited as a reference population. Umbilical cord, peripheral blood and placental (villous and decidua) tissues were collected to evaluate SOD2, PPAR-α and PPARGC-1ß and their respective protein expressions. Data from the reference population confirmed that the three genes and proteins were overexpressed in blood cells of obese compared to eutrophic subjects. Only SOD2 was found upregulated in placental villous (fetal side) tissue of GDM women. Therefore, our findings showed an interaction between the hyperglycemic environment and SOD2 modulation, but also indicated that none of the three genes is useful as potential biomarkers for obesity development.

Defining the Transcriptional Ecosystem.

Fine tuning of the transcriptional program requires the competing action of multiple protein complexes in a well-organized environment. Genome folding creates proximity between genes, leading to accumulation of regulatory factors and formation of local microenvironments. Many roles of this complex organization controlling gene transcription remain to be explored. In this Perspective, we are proposing the existence of a transcriptional ecosystem equilibrium: a mechanism balancing transcriptional regulation between connected genes during environmental disturbances. This model is derived from chromosome architecture studies assigning genes to specific DNA structures and evidence establishing that the transcription machinery and coregulators create dynamic phase separation droplets surrounding active genes. Defining connected genes as ecosystems rather than individuals will cement that transcriptional regulation is a biochemical equilibrium and force a reassessment of direct and indirect responses to environmental disturbances.

Cytological multimarker screening using BMCyt test in waterpipe smokers: an integrative study of cell damage, toxicological and cancer risk.

Waterpipe smoking is an ancient method of tobacco smoking practiced worldwide. There is a common belief that waterpipe smoking is a safer alternative to cigarette, but many studies showed that some toxicants were associated with cancer risk, significantly higher in waterpipe smoking. Thus, this study aimed to evaluate the status of waterpipe smoker's buccal cells and its cancer risk using the buccal micronucleus cytome test. Forty waterpipe smokers (noncigarette smokers) were recruited and paired by gender, age and alcoholic habits with 40 control subjects. One-thousand cells from each individual were analysed and the number of pyknotic cells (PYC), karyolitic cells (KYL), karyorrhetic cells (KHC), condensed chromatin (CC), binucleated cells (BN), basal cells (BC), nuclear buds (NBUD) and differentiated cells (DIFF) were counted. Additionally, 2000 differentiated cells were analysed counting micronucleated cells (MNi) and nuclear buds. We observed an increasing P< 0.05 in all waterpipe smoker's cell parameters, except DIFF (fold-decrease). Only CC showed no differences between groups. The interference in the cell cycle plus DNA damage observed in this study could be responsible for the high number of damaged cells and in death process, showing the importance of our study and the high risk in waterpipe smoking.

Integrative study of cell damage and cancer risk in gas station attendants.

Gas station attendants are potentially exposed to carcinogenic substances. This study aimed to evaluate chronic occupational exposed gas station attendant's according to genetic parameters and its relationship with cancer predisposition. Forty gas station attendants were recruited and paired with 40 control subjects. Thousand cells from each subject were analyzed counting the number of pyknotic (PYC), karyolitic (KYL), karyorrhetic (KHC), condensed chromatin (CC), binucleated (BN), basal cells (BC), Nuclear buds (Nbud), and differentiated cells (DIFF). More 2.000 differentiated cells were analyzed counting micronucleated (MNi) and nuclear buds (NBud). We observed a statistical increase in BC and decrease in DIFF (p < 0.05). PYC, CC, KYL, MN, NBud were statistically increased (p < 0.05). All in all, our data showed elevated DNA damage, chromosomal instability, and cell cycle disturbing in our group of gas station attendants. It is a clear risk for their health in future and could be classified as a cancer predisposition.