Epigenetics of Cutaneous Sarcoma

Epigenetic changes influence various physiological and pathological conditions in the human body. Recent advances in epigenetic studies of the skin have led to an appreciation of the importance of epigenetic modifications in skin diseases. Cutaneous sarcomas are intractable skin cancers, and there are no curative therapeutic options for the advanced forms of cutaneous sarcomas. In this review, we discuss the detailed molecular effects of epigenetic modifications on skin sarcomas, such as dermatofibrosarcoma protuberans, angiosarcoma, Kaposi’s sarcoma, leiomyosarcoma, and liposarcoma. We also discuss the application of epigenetic-targeted therapy for skin sarcomas.

Transcriptome Analysis Reveals Genes Respond to Chlorophyll Deficiency in Green and Yellow Leaves of Chrysanthemum morifolium Ramat

Chlorophyll is vital for photosynthesis to produce sugars and other useful biochemical products in green plants. However, the molecular effects of chlorophyll deficiency in Chrysanthemum are largely unknown. In this study, we identified a bud sport mutant chrysanthemum belonging to the variety ‘Nannong Binyun’, which has yellow branches. Plant physiological studies have shown that the yellow color is revealed due to chlorophyll loss. RNA extracts of yellow and green tissues were analyzed using high-throughput RNA-sequencing, and a total of 11,649 tissue enriched unigenes that respond to chlorophyll deficiency were identified, including 4803 unigenes upregulated in yellow tissues and 6846 unigenes in green tissues. GO analysis revealed that these tissue-enriched genes may involve in the physiological processes of chlorophyll accumulation and photosynthesis. In addition, many DEGs from the families of AP2-EREBP, bHLH, MYB, and FAR1 that are associated with plant development and stress response were detected. Our study found that most of the genes from the GRAS family were downregulated in yellow leaves, indicating their putative roles in stem cell maintenance and possible contribution to leaf size determination.

Gut Metabolite Trimethylamine N-Oxide Protects INS-1 β-Cell and Rat Islet Function under Diabetic Glucolipotoxic Conditions

Serum accumulation of the gut microbial metabolite trimethylamine N-oxide (TMAO) is associated with high caloric intake and type 2 diabetes (T2D). Impaired pancreatic β-cell function is a hallmark of diet-induced T2D, which is linked to hyperglycemia and hyperlipidemia. While TMAO production via the gut microbiome-liver axis is well defined, its molecular effects on metabolic tissues are unclear, since studies in various tissues show deleterious and beneficial TMAO effects. We investigated the molecular effects of TMAO on functional β-cell mass. We hypothesized that TMAO may damage functional β-cell mass by inhibiting β-cell viability, survival, proliferation, or function to promote T2D pathogenesis. We treated INS-1 832/13 β-cells and primary rat islets with physiological TMAO concentrations and compared functional β-cell mass under healthy standard cell culture (SCC) and T2D-like glucolipotoxic (GLT) conditions. GLT significantly impeded β-cell mass and function by inducing oxidative and endoplasmic reticulum (ER) stress. TMAO normalized GLT-mediated damage in β-cells and primary islet function. Acute 40µM TMAO recovered insulin production, insulin granule formation, and insulin secretion by upregulating the IRE1α unfolded protein response to GLT-induced ER and oxidative stress. These novel results demonstrate that TMAO protects β-cell function and suggest that TMAO may play a beneficial molecular role in diet-induced T2D conditions.

Behavioural and molecular effects of alcohol in the stress model of zebrafish

Objectives: Stress and anxiety disorders are common health problems that have been related to an increase in the likelihood of developing addictions, which have individual and social consequences. Although socially acceptable, alcohol is a substance that can generate dependence and abuse. Alcohol misuse, its relationship with stress and its consequences have been studied; however, multiple limitations are placed on clinical research in humans. In this exploratory work, we analysed the behavioural and molecular effects of joint exposure to ethanol and an unpredictable stress protocol (USP) in adult zebrafish. Materials and Methods: Adult zebrafish behaviour was studied employing unpredictable stress and behavioural tests. The tests were performed in stressed and nonstressed animals with and without exposure to known concentrations of alcohol. To evaluate the behaviour, tracking techniques were used on video recordings and parameters such as distance travelled, swimming speed and place preference as well as aggression patterns with mirror proximity tests were measured. In the control and 0.75% alcohol group, the expression of candidate stress-related genes (slc6a4a, slc6a3, comta and bdnf3) was analysed by RT-qPCR. Results: The results showed that concentrations of 0.75% alcohol reduced the locomotor activity of the fish, which can be interpreted as an increase in the anxiolytic effect of alcohol under nonstress conditions. Expression of comta, bdnf3 and slc6a3 was reduced in the stress and stress plus 0.75% ethanol groups and expression of slc6a4a was increased in the stress plus 0.75% alcohol group. Conclusion: Our exploratory work contributes novel insights about the molecular and behavioural effects of the combination of unpredicted stress and alcohol misuse. The USP and ethanol exposure increase anxiety behaviour and reduce the expression of genes involved in brain homeostasis. Future study of other pharmacological compounds and additional genes will be helpful for a deeper understanding of the molecular mechanisms involved in the response to stress and alcohol use.

Exerting the Appropriate Application of Methylprednisolone in Acute Spinal Cord Injury Based on Time Course Transcriptomics Analysis

Methylprednisolone (MP) is an anti-inflammatory drug approved for the treatment of acute spinal cord injuries (SCIs). However, MP administration for SCIs has become a controversial issue while the molecular effects of MP remain unexplored to date. Therefore, delineating the benefits and side effects of MP and determining what MP cannot cure in SCIs at the molecular level are urgent issues. Here, genomic profiles of the spinal cord in rats with and without injury insults, and those with and without MP treatment, were generated at 0, 2, 4, 6, 8, 12, 24, and 48 h post-injury. A comprehensive analysis was applied to obtain three distinct classes: side effect of MP (SEMP), competence of MP (CPMP), and incapability of MP (ICMP). Functional analysis using these genes suggested that MP exerts its greatest effect at 8~12 h, and the CPMP was reflected in the immune response, while SEMP suggested aspects of metabolism, such as glycolysis, and ICMP was on neurological system processes in acute SCIs. For the first time, we are able to precisely reveal responsive functions of MP in SCIs at the molecular level and provide useful solutions to avoid complications of MP in SCIs before better therapeutic drugs are available.

Inferred expression regulator activities suggest genes mediating cardiometabolic genetic signals

Expression QTL (eQTL) analyses have suggested many genes mediating genome-wide association study (GWAS) signals but most GWAS signals still lack compelling explanatory genes. We have leveraged an adipose-specific gene regulatory network to infer expression regulator activities and phenotypic master regulators (MRs), which were used to detect activity QTLs (aQTLs) at cardiometabolic trait GWAS loci. Regulator activities were inferred with the VIPER algorithm that integrates enrichment of expected expression changes among a regulator’s target genes with confidence in their regulator-target network interactions and target overlap between different regulators (i.e., pleiotropy). Phenotypic MRs were identified as those regulators whose activities were most important in predicting their respective phenotypes using random forest modeling. While eQTLs were typically more significant than aQTLs in cis, the opposite was true among candidate MRs in trans. Several GWAS loci colocalized with MR trans-eQTLs/aQTLs in the absence of colocalized cis-QTLs. Intriguingly, at the 1p36.1 BMI GWAS locus the EPHB2 cis-aQTL was stronger than its cis-eQTL and colocalized with the GWAS signal and 35 BMI MR trans-aQTLs, suggesting the GWAS signal may be mediated by effects on EPHB2 activity and its downstream effects on a network of BMI MRs. These MR and aQTL analyses represent systems genetic methods that may be broadly applied to supplement standard eQTL analyses for suggesting molecular effects mediating GWAS signals.