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Triple-negative breast cancer is a molecular subtype of breast cancer, with poor differentiation, high invasion and poor prognosis. Due to the triple-negative breast cancer tumor lack of expression of estrogen receptor, progesterone receptor and human epidermal growth factor 2 receptor, endocrine therapy and targeted therapy are all ineffective, and chemotherapy is the main treatment plan. To improve the survival of patients with triple-negative breast cancer, immunotherapy as an emerging treatment has progressed significantly in triple-negative breast cancer, but the long-term benefit remains unclear. In this paper, we synthesize the latest research results, review the formation mechanism of the tumor immunosuppressive microenvironment of triple-negative breast cancer from immune cells, inflammatory signaling pathways and epigenetic factors, and provide a theoretical basis for the targeted therapy to reverse immunosuppression. [ABSTRACT FROM AUTHOR]

The investigation of environmental effects on clinical measurements using individual samples is challenging because their genetic and environmental factors are different. However, using monozygotic twins (MZ) makes it possible to investigate the influence of environmental factors as they have the same genetic factors within pairs because the difference in the clinical traits within the MZ mostly reflect the influence of environmental factors. We hypothesized that the within‐pair differences in the traits that are strongly affected by genetic factors become larger after genetic risk score (GRS) correction. Using 278 Japanese MZ pairs, we compared the change in within‐pair differences in each of the 45 normalized clinical measurements before and after GRS correction, and we also attempted to correct for the effects of genetic factors to identify Cytosine‐phosphodiester‐Guanine (CpG) sites in DNA sequences with epigenetic effects that are regulated by genetic factors. Five traits were classified into the high heritability group, which was strongly affected by genetic factors. CpG sites could be classified into three groups: regulated only by environmental factors, regulated by environmental factors masked by genetic factors, and regulated only by genetic factors. Our method has the potential to identify trait‐related methylation sites that have not yet been discovered. [ABSTRACT FROM AUTHOR]

Aging is a complex phenomenon symbolized by dynamic loss of tissue homeostasis with diminished cellular function. Along with genetic factors, many epigenetic factors as such lifestyle of an individual also affects aging. The aim of this study was to check the effect of different food habits in the process of aging using an aging biomarker CCL11. An increase in expression of CCL11 was observed in carbohydrate and fat rich foods groups. However, no effect on CCL11 expression was seen in calorie restricted diet groups. Mice fed with carbohydrates rich food gained weight, showed high levels of glucose, HDL and triglycerides while consumption of fat rich food in mice raised serum levels of anti-nuclear antibodies and LDL comparing to the control groups. Different food habits affected differently the serum levels of glucose, anti-nuclear antibodies, and lipid profile. H and E staining of testis and lungs showed that consumption of fat rich food caused emphysema, epithelial degeneration of lungs and aspermatogenesis in testes. Moreover, Calorie restricted diet showed vacuolization in testis. This study shows that food influence aging, expression levels of CCL11, physiology and morphology of lungs and testes in mice. [ABSTRACT FROM AUTHOR]

Epigenetic mechanisms involving DNA methylation and chromatin modifications have emerged as critical facilitators of cancer heterogeneity, substantially affecting cancer development and progression, modulating cell phenotypes, and enhancing or inhibiting cancer cell malignant properties. Not surprisingly, considering the importance of epigenetic regulators in normal stem cell maintenance, many chromatin-related proteins are essential to maintaining the cancer stem cell (CSC)-like state. With increased tumor-initiating capacities and self-renewal potential, CSCs promote tumor growth, provide therapy resistance, spread tumors, and facilitate tumor relapse after treatment. In this review, we characterized the epigenetic mechanisms that regulate the acquisition and maintenance of cancer stemness concerning selected epigenetic factors belonging to the Bromodomain (BrD) family of proteins. An increasing number of BrD proteins reinforce cancer stemness, supporting the maintenance of the cancer stem cell population in vitro and in vivo via the utilization of distinct mechanisms. As bromodomain possesses high druggable potential, specific BrD proteins might become novel therapeutic targets in cancers exhibiting de-differentiated tumor characteristics. [ABSTRACT FROM AUTHOR]

Despite patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) and receiving clopidogrel therapy, some patients still experience major adverse cardiovascular events (MACEs). Clopidogrel resistance, which may be regulated by genetic and epigenetic factors, may play a role in MACEs. This study aimed to determine the association between genetic (CYP2C19 and P2Y12 polymorphisms) and epigenetic (DNA methylation of CYP2C19 and P2Y12 and miRNA-26a expression) factors and their effects on MACEs among post-PCI patients. Post-PCI patients who received a standard dosage of clopidogrel at Harapan Kita Hospital between September 2018 and June 2020 were included in this study. MACEs were observed in patients within 1 year after PCI. Platelet aggregation was assessed using light transmission aggregometry (LTA). DNA methylation of CYP2C19 and P2Y12 was assessed using the bisulfite conversion method. CYP2C19 and P2Y12 polymorphisms and miRNA-26a expression were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). Among a total of 201 subjects, 49.8% were clopidogrel-resistant, and 14.9% experienced MACEs within 1 year after PCI (death was 7.5%). Hypomethylation of CYP2C19 (p = 0.037) and miRNA-26a upregulation (p = 0.020) were associated with clopidogrel resistance. CYP2C19*2/*3 polymorphisms (p = 0.047) were associated with MACEs in 1 year. This study demonstrated that hypomethylation of CYP2C19 and miRNA-26a upregulation increased the risk of clopidogrel resistance in post-PCI patients, but there was no correlation between clopidogrel resistance and MACEs. However, CYP2C19*2/*3 polymorphisms were the factors that predicted MACEs within 1 year.

Silkworm fibroins are natural proteinaceous macromolecules and provide core mechanical properties to silk fibers. The synthesis process of fibroins is posterior silk gland (PSG)-exclusive and appears active at the feeding stage and inactive at the molting stage. However, the molecular mechanisms controlling it remain elusive. Here, the silk gland's physiological and nuclear proteomic features were used to characterize changes in its structure and development from molting to feeding stages. The temporal expression profile and immunofluorescence analyses revealed a synchronous transcriptional on-off mode of fibroin genes. Next, the comparative nuclear proteome of the PSG during the last molting-feeding transition identified 798 differentially abundant proteins (DAPs), including 42 transcription factors and 15 epigenetic factors. Protein-protein interaction network analysis showed a "CTCF-FOX-HOX-SOX" association with activated expressions at the molting stage, suggesting a relatively complex and multifactorial regulation of the PSG at the molting stage. In addition, FAIRE-seq verification indicated "closed" and "open" conformations of fibroin gene promoters at the molting and feeding stages, respectively. Such proteome combined with chromatin accessibility analysis revealed the detailed signature of protein factors involved in the temporal regulation of fibroin synthesis and provided insights into silk gland development as well as silk production in silkworms. • Nuclear proteome profiling of the posterior silk gland at the last molt and intermolt stages was revealed. • Silk glands were subjected to restorable reactive oxygen species during the molting-feeding transition. • The core promoter region of fibroin genes exhibited synchronous "closed" and "open" conformations. • 42 transcription factors and 15 epigenetic factors might be associated with the temporal regulation of fibroin synthesis. [ABSTRACT FROM AUTHOR]

Objective: To explore the targeting relationship between miRNA and epigenetic factors related to the prognosis of hepatocellular carcinoma (HCC), and to identify the potential impact of miRNA targeted epigenetic factors on the prognosis of HCC. Methods: The mRNA and miRNA sequencing data of all HCC samples were downloaded from the tumor Genome Atlas (TCGA) database, and the R program was used to analyze the difference of the sequencing data. The data of survival time, survival status and differential expression of miRNA were combined, and the risk score model of miRNA was constructed by univariate and multivariate Cox regression. The miRNA target genes and all the corresponding Epigenetic factors were predicted, and the differentially expressed Epigenetic factors (DEEFs) were screened. Then, the regulatory network of miRNA targeting deefs was established, the apparent factors in the network were enriched and analyzed, and the core genes in the protein-protein interaction (PPI) network and selection network were constructed. Finally, the relationship between the apparent factors and the prognosis of patients was analyzed and verified by Kaplan Meier (K-M) method. Results: 305 differentially expressed miRNAs were identified using EDGE algorithm. After Cox analysis, hsa-miR-139-5p, hsa-miR-101-3p and hsa-miR-7-5p (miR-139-5p, miR-101-3p and miR-7-5p) were finally screened as the Overall survival of HCC patients (Overall survival, OS). In addition, 34 DEEFs targeted by miRNAs were identified, among which EZH2, PKM, HJURP and CHEK1 had a significant impact on the survival of hepatocellular carcinoma. Conclusion: In this study, we successfully established a prognostic model of hepatocellular carcinoma miRNA-targeted epigenetics, and screened out epigenetic factors that are significantly related to the prognosis of hepatocellular carcinoma. It provides new potential prognostic biomarkers and therapeutic targets for HCC treatment, and lays a theoretical foundation for the follow-up basic research of HCC. [ABSTRACT FROM AUTHOR]

With a view to comprehensive processing of coal and its ash and slag wastes, the metallogenic specialization of Kuznetsk Basin coal is assessed for different geological and economic regions and for coal of different metamorphic stages. The content of nonferrous and rare metals in Kuznetsk Basin coal and Kazakh coal is compared. The prospects for extracting valuable metals from coal and, in particular, its waste are assessed. Nonferrous and rare metals may accumulate in the initial coal (the syngenetic factor) and coal may be associated with the action of metal–hydrogen–carbon fluids on tectonically permeable sections of the coal bed (the endogenetic factor). In addition, elevated metal content in the coal may be associated with the proximity of several coal fields (the epigenetic factor). In the Kuznetsk Basin, the endogenetic and epigenetic factors are most significant. The metamorphic stage of the coal has less effect on the metal content. Metals present in low concentrations are most often the result of accumulation in the initial coal (the syngenetic factor). The content of toxic metals in the coal is below the limiting permissible concentration. [ABSTRACT FROM AUTHOR]

Congenital heart disease is the most common birth defect worldwide. Defective cardiac myogenesis is either a major presentation or associated with many types of congenital heart disease. Non-myocardial tissues, including endocardium and epicardium, function as a supporting hub for myocardial growth and maturation during heart development. Recent research findings suggest an emerging role of epigenetics in nonmyocytes supporting myocardial development. Understanding how growth signaling pathways in non-myocardial tissues are regulated by epigenetic factors will likely identify new disease mechanisms for congenital heart diseases and shed lights for novel therapeutic strategies for heart regeneration. [ABSTRACT FROM AUTHOR]

Abstract Background Endothelial cell (EC) dysfunctions, including turnover enrichment, gap junction disruption, inflammation, and oxidation, play vital roles in the initiation of vascular disorders and atherosclerosis. Hemodynamic forces, i.e., atherprotective pulsatile (PS) and pro-atherogenic oscillatory shear stress (OS), can activate mechanotransduction to modulate EC function and dysfunction. This review summarizes current studies aiming to elucidate the roles of epigenetic factors, i.e., histone deacetylases (HDACs), non-coding RNAs, and DNA methyltransferases (DNMTs), in mechanotransduction to modulate hemodynamics-regulated EC function and dysfunction. Main body of the abstract OS enhances the expression and nuclear accumulation of class I and class II HDACs to induce EC dysfunction, i.e., proliferation, oxidation, and inflammation, whereas PS induces phosphorylation-dependent nuclear export of class II HDACs to inhibit EC dysfunction. PS induces overexpression of the class III HDAC Sirt1 to enhance nitric oxide (NO) production and prevent EC dysfunction. In addition, hemodynamic forces modulate the expression and acetylation of transcription factors, i.e., retinoic acid receptor α and krüppel-like factor-2, to transcriptionally regulate the expression of microRNAs (miRs). OS-modulated miRs, which stimulate proliferative, pro-inflammatory, and oxidative signaling, promote EC dysfunction, whereas PS-regulated miRs, which induce anti-proliferative, anti-inflammatory, and anti-oxidative signaling, inhibit EC dysfunction. PS also modulates the expression of long non-coding RNAs to influence EC function. i.e., turnover, aligmant, and migration. On the other hand, OS enhances the expression of DNMT-1 and -3a to induce EC dysfunction, i.e., proliferation, inflammation, and NO repression. Conclusion Overall, epigenetic factors play vital roles in modulating hemodynamic-directed EC dysfunction and vascular disorders, i.e., atherosclerosis. Understanding the detailed mechanisms through which epigenetic factors regulate hemodynamics-directed EC dysfunction and vascular disorders can help us to elucidate the pathogenic mechanisms of atherosclerosis and develop potential therapeutic strategies for atherosclerosis treatment.

To identify PBMC-expressed genes significant for RA, and to ascertain their upstream regulatory factors, as well as downstream functional effects relevant to RA pathogenesis. We performed peripheral blood mononuclear cells (PBMCs) transcriptome-wide mRNA expression profiling in a case–control discovery sample. Differentially expressed genes (DEGs) were identified and validated in PBMCs in independent samples. We also generated genome-wide SNP genotyping data, and collected miRNA expression data and DNA methylation data from PBMCs of the discovery sample. Pearson correlation analyses were conducted to identify miRNAs/DNA methylations influencing DEG expression. Association analyses were conducted to identify expression-regulating SNPs. The key DEG, SAMD9, which was reported to function as a tumor suppressor gene, was assessed for its effects on T cell proliferation, apoptosis, and inflammatory cytokine expression. A total of 181 DEGs (Fold Change ≥ 2.0, Bonferroni adjusted p ≤ 0.05) were discovered in PBMCs. Four DEGs (SAMD9, CKLF, PARP9, and GUSB), upregulated with RA, were validated independently in PBMCs. Specifically, SAMD9 mRNA expression level was significantly upregulated in PHA-activated Jurkat T cells in vitro, and correlated with 8 miRNAs and associated with 22 SNPs in PBMCs in vivo. Knockdown of SAMD9 could transiently promote Jurkat T cell proliferation within 48 h and significantly induce TNF-α and IL-8 expression in T cells. SAMD9 expression is (epi-) genetically regulated, and significantly upregulated in PBMCs in RA patients and in activated T cells in vitro. SAMD9 might serve as a T cell activation marker but act as an anti-inflammatory factor. [ABSTRACT FROM AUTHOR]

Keywords: computational method; complex disease; environmental factor; disease gene; genetic factor; epigenetic factor EN computational method complex disease environmental factor disease gene genetic factor epigenetic factor N.PAG N.PAG 3 05/17/21 20210421 NES 210421 With the advances of sequencing and experimental techniques, the molecular mechanisms of human Mendelian diseases have been more or less elucidated. Sun et al. proposed a mathematical model based on matrix decomposition, named MFMDA, to identify potential miRNA-disease associations by integrating known miRNA and disease-related data, similarities between miRNAs and between diseases. Guan et al. constructed cell type-specific predictive models for autism spectrum disorder (ASD) based on individual genes and gene sets, respectively, to screen cell type-specific ASD-associated genes and gene sets. [Extracted from the article]

The postnatal mammalian olfactory epithelium (OE) represents a major aspect of the peripheral olfactory system. It is a pseudostratified tissue that originates from the olfactory placode and is composed of diverse cells, some of which are specialized receptor neurons capable of transducing odorant stimuli to afford the perception of smell (olfaction). The OE is known to offer a tractable miniature model for studying the systematic generation of neurons and glia that typify neural tissue development. During OE development, stem/progenitor cells that will become olfactory sensory neurons and/or non-neuronal cell types display fine spatiotemporal expression of neuronal and non-neuronal genes that ensures their proper proliferation, differentiation, survival, and regeneration. Many factors, including transcription and epigenetic factors, have been identified as key regulators of the expression of such requisite genes to permit normal OE morphogenesis. Typically, specific interactive regulatory networks established between transcription and epigenetic factors/cofactors orchestrate histogenesis in the embryonic and adult OE. Hence, investigation of these regulatory networks critical for OE development promises to disclose strategies that may be employed in manipulating the stepwise transition of olfactory precursor cells to become fully differentiated and functional neuronal and non-neuronal cell types. Such strategies potentially offer formidable means of replacing injured or degenerated neural cells as therapeutics for nervous system perturbations. This review recapitulates the developmental cellular diversity of the olfactory neuroepithelium and discusses findings on how the precise and cooperative molecular control by transcriptional and epigenetic machinery is indispensable for OE ontogeny. [ABSTRACT FROM AUTHOR]

Epigenetic regulation has long been recognized as a significant factor in various biological processes, such as development, transcriptional regulation, spermatogenesis, and chromosome stabilization. Epigenetic alterations lead to many human diseases, including cancer, depression, autism, and immune system defects. Although efforts have been made to identify epigenetic regulators, it remains a challenge to systematically uncover all the components of the epigenetic regulation in the genome level using experimental approaches. The advances of constructing protein–protein interaction (PPI) networks provide an excellent opportunity to identify novel epigenetic factors computationally in the genome level. In this study, we identified potential epigenetic factors by using a computational method that applied the random walk with restart (RWR) algorithm on a protein–protein interaction (PPI) network using reported epigenetic factors as seed nodes. False positives were identified by their specific roles in the PPI network or by a low-confidence interaction and a weak functional relationship with epigenetic regulators. After filtering out the false positives, 26 candidate epigenetic factors were finally accessed. According to previous studies, 22 of these are thought to be involved in epigenetic regulation, suggesting the robustness of our method. Our study provides a novel computational approach which successfully identified 26 potential epigenetic factors, paving the way on deepening our understandings on the epigenetic mechanism. [ABSTRACT FROM AUTHOR]

Low temperature is a major adverse environmental factor that impairs petunia growth and development. To better understand the molecular mechanisms of cold stress adaptation of petunia plants, a quantitative proteomic analysis using iTRAQ technology was performed to detect the effects of cold stress on protein expression profiles in petunia seedlings which had been subjected to 2°C for 5d. Of the 2,430 proteins whose levels were quantitated, a total of 117 proteins were discovered to be differentially expressed under low temperature stress in comparison to unstressed controls. As an initial study, 44 proteins including well known and novel cold-responsive proteins were successfully annotated. By integrating the results of two independent Gene Ontology (GO) enrichment analyses, seven common GO terms were found of which oxidation-reduction process was the most notable for the cold-responsive proteins. By using the subcellular localization tool Plant-mPLoc predictor, as much as 40.2% of the cold-responsive protein group was found to be located within chloroplasts, suggesting that the chloroplast proteome is particularly affected by cold stress. Gene expression analyses of 11 cold-responsive proteins by real time PCR demonstrated that the mRNA levels were not strongly correlated with the respective protein levels. Further activity assay of anti-oxidative enzymes showed different alterations in cold treated petunia seedlings. Our investigation has highlighted the role of antioxidation mechanisms and also epigenetic factors in the regulation of cold stress responses. Our work has provided novel insights into the plant response to cold stress and should facilitate further studies regarding the molecular mechanisms which determine how plant cells cope with environmental perturbation.

Cancer is the manifestation of changes and mutations in genetic and epigenetic levels. Non-coding RNAs (ncRNAs) are commonly dysregulated in disease pathogenesis, and their role in cancer has been well-documented. The ncRNAs regulate various molecular pathways and mechanisms in cancer that can lead to induction/inhibition of carcinogenesis. Autophagy is a molecular "self-digestion" mechanism its function can be pro-survival or pro-death in tumor cells. The aim of the present review is to evaluate the role of ncRNAs in regulating autophagy in gastrointestinal tumors. The role of the ncRNA/autophagy axis in affecting the progression of gastric, liver, colorectal, pancreatic, esophageal, and gallbladder cancers is investigated. Both ncRNAs and autophagy mechanisms can function as oncogenic or onco-suppressor and this interaction can determine the growth, invasion, and therapy response of gastrointestinal tumors. ncRNA/autophagy axis can reduce/increase the proliferation of gastrointestinal tumors via the glycolysis mechanism. Furthermore, related molecular pathways of metastasis, such as EMT and MMPs, are affected by the ncRNA/autophagy axis. The response of gastrointestinal tumors to chemotherapy and radiotherapy can be suppressed by pro-survival autophagy, and ncRNAs are essential regulators of this mechanism. miRNAs can regulate related genes and proteins of autophagy, such as ATGs and Beclin-1. Furthermore, lncRNAs and circRNAs down-regulate miRNA expression via sponging to modulate the autophagy mechanism. Moreover, anti-cancer agents can affect the expression level of ncRNAs regulating autophagy in gastrointestinal tumors. Therefore, translating these findings into clinics can improve the prognosis of patients. [Display omitted] [ABSTRACT FROM AUTHOR]

The role of cGMP (cyclic guanosine monophosphate) in the suppression of apoptosis in preantral and preovulatory follicles has been established. But the underlying mechanisms have not yet been established. The present study has been focused on revealing the mechanisms involved in the cGMP mediated suppression of apoptosis and in survival of ovarian follicle. cGMP reduces calcium burden of the cell by mediating Ca channels, BK (Big Potassium) channels, phosphatidylinositol 3-kinase (PI3K)/Akt pathway thus, prevents the mitochondrial membrane pore formation and apoptosis. cGMP induces the expression of Trx (thioredoxin) protein and prevents the TNF-α (Tumour Necrosis factor) induced apoptosis. cGMP also induces the expression of cytoskeleton proteins which are involved in heterogeneous distribution of mitochondria and there by reduces the Ca burden and apoptosis. Histone 3 lysine 4 methyltransferase (MLL2) is an epigenetic factor inhibits the transcription of genes involved apoptosis which acts as co-activator of Estrogen receptor-α. In conclusion the present review predicts some mechanisms underlying the cGMP mediated suppression of apoptosis in ovarian follicles. [ABSTRACT FROM AUTHOR]

Despite patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) and receiving clopidogrel therapy, some patients still experience major adverse cardiovascular events (MACEs). Clopidogrel resistance, which may be regulated by genetic and epigenetic factors, may play a role in MACEs. This study aimed to determine the association between genetic ( CYP2C19 and P2Y12 polymorphisms) and epigenetic (DNA methylation of CYP2C19 and P2Y12 and miRNA-26a expression) factors and their effects on MACEs among post-PCI patients. Post-PCI patients who received a standard dosage of clopidogrel at Harapan Kita Hospital between September 2018 and June 2020 were included in this study. MACEs were observed in patients within 1 year after PCI. Platelet aggregation was assessed using light transmission aggregometry (LTA). DNA methylation of CYP2C19 and P2Y12 was assessed using the bisulfite conversion method. CYP2C19 and P2Y12 polymorphisms and miRNA-26a expression were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). Among a total of 201 subjects, 49.8% were clopidogrel-resistant, and 14.9% experienced MACEs within 1 year after PCI (death was 7.5%). Hypomethylation of CYP2C19 ( p = 0.037) and miRNA-26a upregulation ( p = 0.020) were associated with clopidogrel resistance. CYP2C19 * 2/ * 3 polymorphisms ( p = 0.047) were associated with MACEs in 1 year. This study demonstrated that hypomethylation of CYP2C19 and miRNA-26a upregulation increased the risk of clopidogrel resistance in post-PCI patients, but there was no correlation between clopidogrel resistance and MACEs. However, CYP2C19 * 2/ * 3 polymorphisms were the factors that predicted MACEs within 1 year., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Giantini, Timan, Dharma, Sukmawan, Setiabudy, Alwi, Harahap, Listiyaningsih, Partakusuma, Tansir, Sahar and Hidayat.)

From onset to progression, cancer is a ailment that might take years to grow. All common epithelial malignancies, have a long latency period, frequently 20 years or more, different gene may contain uncountable mutations if they are clinically detectable. MicroRNAs (miRNAs) are around 22nt non-coding RNAs that control gene expression sequence-specifically through translational inhibition or messenger degradation of RNA (mRNA). Epigenetic processes of miRNA control genetic variants through genomic DNA methylation, post-translation histone modification, rework of the chromatin, and microRNAs. The field of miRNAs has opened a new era in understanding small non-coding RNAs since discovering their fundamental mechanisms of action. MiRNAs have been found in viruses, plants, and animals through molecular cloning and bioinformatics approaches. Phytochemicals can invert the epigenetic aberrations, a leading cause of the cancers of various organs, and act as an inhibitor of these changes. The advantage of phytochemicals is that they only function on cells that cause cancer without affecting normal cells. Phytochemicals appear to play a significant character in modulating miRNA expression, which is linked to variations in oncogenes, tumor suppressors, and cancer-derived protein production, according to several studies. In addition to standard anti-oxidant or anti-inflammatory properties, the initial epigenetic changes associated with cancer prevention may be modulated by many polyphenols. In correlation with miRNA and epigenetic factors to treat cancer some of the phytochemicals, including polyphenols, curcumin, resveratrol, indole-3-carbinol are studied in this article. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most common malignancies in the world and has a high mortality rate. It is believed that dysfunction in the expression of mucins and aberrant expression of some lncRNAs are associated with the occurrence and development of CRC. Therefore, the aim of the present study was to investigate the expression of MUC15, MUC16, MUC20, PCAT1, CCAT1 and HOTAIR genes in colorectal cancer and its relationship with clinicopathological variables. This research was prospective case-control study. Tumors from CRC patients were collected from the Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. RNA extraction and cDNA synthesis were performed using the corresponding kits. The gene primer was designed and RT-PCR was used to evaluate gene expression. The t-test and ANOVA were employed to examine the differences between groups. Data analysis was performed using Prism8 software. The results of the present study showed that the expression of MUC15 (P = 0.0012), MUC20 (P = 0.009) and CCAT1 (P = 0.001) genes in patients with colorectal cancer were significantly different from tumor margin samples. There were also associations between the expression of the studied genes and clinicopathological variables such as grade and stage of colorectal cancer tumor as well as the age of the patients. The area under the curves (AUC) for the MUC15 0.953 (95% CI 7565–0.9897, P = 0.0003), MUC20 0.782 (95% CI 0.6163–0.9482, P = 0.008) and CCAT1 0.917 (95% CI 0.8015–1, P = 0.0003) were calculated by ROC analysis. The current experiment revealed changes in expression level of mucin genes and lncRNAs in CRC and its different stages, showing that they can be considered as biomarkers for diagnosis of this cancer. [ABSTRACT FROM AUTHOR]

Purpose: To investigate if antituberculosis medication including ethambutol could be a possible epigenetic factor in visual loss in Leber's hereditary optic neuropathy (LHON). Methods: The authors reviewed the medical records of 46 patients registered at Bundang Seoul National University Hospital from 2002 to 2006, who developed the typical clinical neuro-ophthalmologic features of LHON and possessed a mtDNA mutation at nucleotide 11778, 14484, 3460 or 4171. Results: Three of the 46 patients developed visual loss while taking antituberculosis medication. These three patients had the mtDNA 11778 mutation with a mean age of 32.7 years at the onset of visual loss, whereas the mean age of other 43 patients was 21.2 years. One of these three patients was female. Conclusion: Antituberculosis medication may be an epigenetic factor of LHON in patients with a primary LHON mutation. This risk should be recognized by physicians and LHON carriers. [ABSTRACT FROM AUTHOR]

Autoimmune diseases altogether affect approximately 5% of the population in Western countries, with a higher prevalence in women. Exploring the biological differences between sexes, great attention was focused on hormones and, more recently, on fetal mircochimerism, without reaching definitive evidence. Genetic factors are known to be crucial determinants of susceptibility, as shown by family and twin studies, although no specific genes predisposing women to autoimmunity have been identified thus far. In this article, we review recent data regarding X-chromosome abnormalities, such as inactivation patterns and X monosomy, that characterize some female-predominant autoimmune diseases. We believe that future high-throughput tools will help to identify specific clusters of genes on the sex chromosomes that are candidates for disease susceptibility or resistance. [ABSTRACT FROM AUTHOR]

Development of an organism is a multi-dimensional process leading to the generation of complex species-specific structures. This specificity suggests machine-like organisation. The uneven distribution (gradient) of soluble substances (morphogens) and specific receptor-ligand interactions are known to cause differential gene expression. Therefore gradients of morphogens are used as a causal explanation of developmental processes. However each attempt to describe development causally should take into account both the local fine organisation and global robustness of morphogenesis. The classical view of the role of morphogens will be critically considered and possible alternative proposed. The core idea of my proposal is that the main function of morphogenetic substances could be a context dependent modification of cell behaviour. Both history and different features of morphogenetic fields create the framework for the activity of morphogenes. [ABSTRACT FROM AUTHOR]

The factors governing the pattern formation process in the early morphogenesis of a marine colonial hydroid, Dynamena pumila, have been studied. Two different types of morphogenesis have been distinguished. Morphogenesis of the first type goes on via changes in cell shape and cell axis orientation, while morphogenesis of the second type is based upon the active coordinated cell movements associated with cell rearrangements. It was shown that morphogenesis of both types can be considered as cascades in which any event is a consequence of the previous one. The spatial structure of each developmental stage contains information about the direction and the initial conditions of further morphogenesis. So, an "epigenetic program" of morphogenesis gradually originates in the course of development and provides the stable reproduction of spatial structures. It is reasonable to consider the activity of epigenetic factors guiding Dynamena morphogenesis (geometry/topology of an embryo, heterogeneity of an embryo spatial structure, configuration of the field of mechanical stresses of the embryo surface) as "morphomechanical programming" of morphogenesis. [ABSTRACT FROM AUTHOR]

Abstract: The T5P mutation in human γC-crystallin produces a lens cataract. Here, we have investigated the effects of the T5P mutation upon the aggregation of γC-crystallin in vitro and in transfected cells. By sedimentation assay and sucrose gradient centrifugation, the mutation significantly increased the aggregation of the protein and reduced dramatically its solubility in vitro. Similar effects were seen when T5P γC-crystallin was transfected into tissue culture cells, resulting in the formation of cytoplasmic aggregates of T5P γC-crystallin. Interestingly, the major lenticular protein chaperones, αA- and αB-crystallin, increased the solubility of the T5P γC-crystallin both in vitro and in transfected cells. More importantly, the size of the T5P γC-crystallin aggregates were also significantly reduced in the presence of the lenticular chaperones. These data therefore suggest a dual role for these chaperones in maintaining transparency in the lens. The first is that these protein chaperones increase the proportion of the soluble T5P γC-crystallin and the second is that they also reduce light scatter by reducing the aggregate size of T5P γC-crystallin. Both activities could modify the cataract phenotype and help explain the observed variability reported for identical γ-crystallin mutations, which identify cataract as a polygenic disease. [Copyright &y& Elsevier]

Over the past decades, the new opportunity of space flights has revealed the importance of gravity as a mechanical constraint for terrestrial organisms as well as its influence on the somatosensory system. The lack of gravitational reference in orbital flight induces changes in equilibrium, with major modifications involving neuromorphological and physiological adaptations. However, few data have illustrated the putative effect of gravity on sensory vestibular epithelial development. We asked if gravity, the primary stimulus of utricles could act as an epigenetic factor. As sensorial deprivation linked to weightlessness is technically difficult, we used a ground-based centrifuge to increase the gravitational vector, in order to hyperstimulate the vestibule. In this study, 3 days after mating, pregnant females were submitted to hypergravity, 2 g (HG). Their embryos were raised, born and postnatally developed under HG. The establishment of connections between primary vestibular afferent neurons and hair cells in the utricle of these young rats was followed from birth to postnatal day 6 (PN6) and compared to embryos developed in normogravity (NG): Immunocytochemistry for neurofilaments and microvesicles revealed the differential effects of gravity on the late neuritogenic and synaptogenic processes in utricles. Taking type I hair cell innervation as a criterion of maturation, we found that primary afferent fibres reached the vestibular epithelium and enveloped hair cells in the same way, both under NG and HG. Thus, this phenomenon of leading growth cones to their epithelial target appears to be dependent on intrinsic genetic properties and not on an external stimulus. In contrast, the maturation of connection processes between type 1 hair cells and the afferent calyx, concerning specifically the microvesicles at their apex, was delayed under HG. Therefore, gravity appears to be an epigenetic factor influencing the late maturation of utricles. These differential effects of altered gravity on the development of the vestibular epithelium are discussed. [Copyright &y& Elsevier]

SETDB1, a histone methyltransferase that trimethylates histone H3 on lysine 9, promotes development of several tumor types. We investigated whether SETDB1 contributes to development of pancreatic ductal adenocarcinoma (PDAC). We performed studies with Ptf1a Cre ; Kras G12D ; Setdb1 f/f , Ptf1a Cre ; Kras G12D ; Trp53 f/+ ; Setdb1 f/f , and Ptf1a Cre ; Kras G12D ; Trp53 f/f ; Setdb1 f/f mice to investigate the effects of disruption of Setdb1 in mice with activated KRAS-induced pancreatic tumorigenesis, with heterozygous or homozygous disruption of Trp53. We performed microarray analyses of whole-pancreas tissues from Ptf1a Cre ; Kras G12D ; Setdb1 f/f , and Ptf1a Cre ; Kras G12D mice and compared their gene expression patterns. Chromatin immunoprecipitation assays were performed using acinar cells isolated from pancreata with and without disruption of Setdb1. We used human PDAC cells for SETDB1 knockdown and inhibitor experiments. Loss of SETDB1 from pancreas accelerated formation of premalignant lesions in mice with pancreata that express activated KRAS. Microarray analysis revealed up-regulated expression of genes in the apoptotic pathway and genes regulated by p53 in SETDB1-deficient pancreata. Deletion of Setdb1 from pancreas prevented formation of PDACs, concomitant with increased apoptosis and up-regulated expression of Trp53 in mice heterozygous for disruption of Trp53. In contrast, pancreata of mice with homozygous disruption of Trp53 had no increased apoptosis, and PDACs developed. Chromatin immunoprecipitation revealed that SETDB1 bound to the Trp53 promoter to regulate its expression. Expression of an inactivated form of SETDB1 in human PDAC cells with wild-type TP53 resulted in TP53-induced apoptosis. We found that the histone methyltransferase SETDB1 is required for development of PDACs, induced by activated KRAS, in mice. SETDB1 inhibits apoptosis by regulating expression of p53. SETDB1 might be a therapeutic target for PDACs that retain p53 function. [ABSTRACT FROM AUTHOR]

Methyl-CpG binding protein 2, MECP2, which binds to methylated regions of DNA to regulate transcription, is expressed by hepatic stellate cells (HSCs) and is required for development of liver fibrosis in mice. We investigated the effects of MECP2 deletion from HSCs on their transcriptome and of phosphorylation of MECP2 on HSC phenotype and liver fibrosis. We isolated HSCs from Mecp2 –/y mice and wild-type (control) mice. HSCs were activated in culture and used in array analyses of messenger RNAs and long noncoding RNAs. Kyoto Encyclopedia of Genes and Genomes pathway analyses identified pathways regulated by MECP2. We studied mice that expressed a mutated form of Mecp2 that encodes the S80A substitution, MECP2S80, causing loss of MECP2 phosphorylation at serine 80. Liver fibrosis was induced in these mice by administration of carbon tetrachloride, and liver tissues and HSCs were collected and analyzed. MECP2 deletion altered expression of 284 messenger RNAs and 244 long noncoding RNAs, including those that regulate DNA replication; are members of the minichromosome maintenance protein complex family; or encode CDC7, HAS2, DNA2 (a DNA helicase), or RPA2 (a protein that binds single-stranded DNA). We found that MECP2 regulates the DNA repair Fanconi anemia pathway in HSCs. Phosphorylation of MECP2S80 and its putative kinase, HAS2, were induced during transdifferentiation of HSCs. HSCs from MECP2S80 mice had reduced proliferation, and livers from these mice had reduced fibrosis after carbon tetrachloride administration. In studies of mice with disruption of Mecp2 or that expressed a form of MECP2 that is not phosphorylated at S80, we found phosphorylation of MECP2 to be required for HSC proliferation and induction of fibrosis. In HSCs, MECP2 regulates expression of genes required for DNA replication and repair. Strategies to inhibit MECP2 phosphorylation at S80 might be developed for treatment of liver fibrosis. [ABSTRACT FROM AUTHOR]

Aim: To identify epigenetically regulated network of genes in peripheral blood mononuclear cells significant for rheumatoid arthritis (RA). Methods: Differentially expressed genes (DEGs) and their associated differentially expressed miRNAs and differentially methylated positions (DMPs) were identified. Causal inference test (CIT) identified the causal regulation chains. The analyses, for example, weighted gene co-expression network (WGCNA), protein-protein interaction and functional enrichment, evaluated interaction patterns among the DEGs and the associated epigenetic factors. Results: A total of 181 DEGs were identified. The DEGs were significantly regulated by DMPs and/or differentially expressed miRNAs. Causal inference test analyses identified 18 causal chains of DMP-DEG-RA and 16 intermediate DEGs enriched in 'protein kinase inhibitor activity'. BTN2A1 was co-expressed with other 9 intermediate genes and 11 known RA-associated genes and played a pivotal role in the co-expression network. Conclusion: Epigenetically regulated network of genes in peripheral blood mononuclear cells (PBMC) contributed to RA. The causal DMPs and key intermediate genes may serve as potential biomarkers for RA.

Aging is a natural, time-dependent process characterized by irreversible changes in the molecules, cells, tissues, and organs. It occurs as a result of cumulative damage at different levels of the organization, in particular by damaging proteins and DNA. There is no single definition, nor a unique attitude about when and how age arises and what are its causes. The process is extremely complex and most likely a consequence of the effects of different mechanisms (not only genetic but also acquired) that lead to disrupt homeostasis, reduce stress resistance and the more frequent occurrence of the disease. There are many classifications of theories about aging and they often contradict one another. No one theory is sufficiently able to explain the process of aging. The aim of this work is to analyze the different aspects, main characteristics of the aging, individual differences in the speed of this process and theories about the mechanisms of aging., (Copyright: © 2016 by Fabrizio Serra editore, Pisa · Roma.)

Human embryonic stem cells (hESCs) have been used to derive trophoblasts through differentiation in vitro. Intriguingly, mouse ESCs are prevented from differentiation to trophoblasts by certain epigenetic factor proteins such as Dnmt1, thus necessitating the study of epigenetic factor proteins during hESC differentiation to trophoblasts. We used stable isotope labeling by amino acids in cell culture and quantitative proteomics to study changes in the nuclear proteome during hESC differentiation to trophoblasts and identified changes in the expression of 30 epigenetic factor proteins. Importantly, the DNA methyltransferases DNMT1, DNMT3A, and DNMT3B were downregulated. Additionally, we hypothesized that nuclear proteomics of hESC-derived trophoblasts may be used for screening epigenetic factor proteins expressed by primary trophoblasts in human placental tissue. Accordingly, we conducted immunohistochemistry analysis of six epigenetic factor proteins identified from hESC-derived trophoblasts-DNMT1, DNMT3B, BAF155, BAF60A, BAF57, and ING5-in 6-9 week human placentas. Indeed, expression of these proteins was largely, though not fully, consistent with that observed in 6-9 week placental trophoblasts. Our results support the use of hESC-derived trophoblasts as a model for placental trophoblasts, which will enable further investigation of epigenetic factors involved in human trophoblast development.

Low temperature is a major adverse environmental factor that impairs petunia growth and development. To better understand the molecular mechanisms of cold stress adaptation of petunia plants, a quantitative proteomic analysis using iTRAQ technology was performed to detect the effects of cold stress on protein expression profiles in petunia seedlings which had been subjected to 2°C for 5 days. Of the 2430 proteins whose levels were quantitated, a total of 117 proteins were discovered to be differentially expressed under low temperature stress in comparison to unstressed controls. As an initial study, 44 proteins including well known and novel cold-responsive proteins were successfully annotated. By integrating the results of two independent Gene Ontology (GO) enrichment analyses, seven common GO terms were found of which "oxidation-reduction process" was the most notable for the cold-responsive proteins. By using the subcellular localization tool Plant-mPLoc predictor, as much as 40.2% of the cold-responsive protein group was found to be located within chloroplasts, suggesting that the chloroplast proteome is particularly affected by cold stress. Gene expression analyses of 11 cold-responsive proteins by real time PCR demonstrated that the mRNA levels were not strongly correlated with the respective protein levels. Further activity assay of anti-oxidative enzymes showed different alterations in cold treated petunia seedlings. Our investigation has highlighted the role of antioxidation mechanisms and also epigenetic factors in the regulation of cold stress responses. Our work has provided novel insights into the plant response to cold stress and should facilitate further studies regarding the molecular mechanisms which determine how plant cells cope with environmental perturbation. The data have been deposited to the ProteomeXchange with identifier PXD002189.