Epigenetic Regulatory Factors Research Articles

Diagnostic potential of miRNA-135A1 in human papillomavirus associated cervical lesions

Introduction. Human papillomavirus (HPV) infection with high-risk HPVs is an etiological factor in the development of cervical cancer, with HPV type 16 (HPV16) being the most common. The mechanisms leading to disruption of viral oncogene expression and initiation of epithelial cell transformation are poorly understood. Epigenetic regulatory factors, including cellular miRNAs, may play an important role in HPV-induced carcinogenesis, and aberrantly expressed miRNAs may be promising markers for the diagnosis of HPV-associated lesions.Aim. To search for miRNAs involved in the pathogenesis of HPV16-associated cervical cancer and to evaluate their diagnostic potential for the detection of cervical cancer and precancerous lesions.Materials and methods. MiRNA expression in clinical samples was assessed by both next generation sequencing and quantitative stem-loop polymerase chain reaction (sl-qPCR). Plasma miRNAs from patients with precancerous and cancerous lesions and healthy donors were analyzed using sl-qPCR. Loss of heterozygosity in cervical cancer samples was assessed by copy number ratio of MIR135A1 and ACTB genes. A total of 67 patients with cervical cancer, 21 with precancerous cervical lesions and 24 healthy donors were included in the study. The effect of DNA methylation on miRNA-135A1 expression was evaluated after treatment with a demethylating agent of the cervical HPV16-positive SiHa cell line. Changes in the expression of the HPV16 E6 oncogene were analyzed after transfection with synthetic analogues of the mature forms of miRNA-135А1 (miRNA-135a-3p and miRNA-135a-5p).Results. A significant decrease in the expression of miRNA-135A1 and miRNA-135A2 was detected in tumor tissue samples from HPV16-positive cervical cancer, which was confirmed by sl-qPCR in an independent panel of tumor samples. A decrease in miRNA-135A1 expression was shown to result from both loss of heterozygosity of the gene and aberrant DNA methylation. Transfection of mature forms of miRNA-135A1 into SiHa cells resulted in decreased expression of the E6 oncogene of HPV16. Blood plasma samples from patients with cervical cancer and precancerous lesions showed lower levels of miRNA-135a-3p than healthy donors, and ROC analysis indicated its high diagnostic potential.Conclusion. Levels of miRNA-135A1 are significantly reduced in cervical lesions, both in tumor tissue and plasma, and the ability of this miRNA to suppress the expression of the HPV16 E6 oncogene suggests its oncosuppressive properties. Thus, miRNA-135A1 can be used as a promising new marker for the diagnosis of HPV-associated lesions.

The Advances in the Development of Epigenetic Modifications Therapeutic Drugs Delivery Systems.

Epigenetic dysregulation can significantly trigger the onset and progression of various diseases, epigenetic therapy is a new treatment strategy by changing DNA methylation, histone modification, N6-methyladenosine, chromatin modification and other epigenetic modifications to regulate gene expression levels for therapeutic purposes. However, small-molecule epigenetic drugs face challenges in disease treatment, such as lack of selectivity, limited therapeutic efficacy, and insufficient safety. Nanomedicine delivery systems offer significant advantages in addressing these issues by enhancing drug targeting, improving bioavailability, and reducing nonspecific distribution. This help minimize side effects while increasing both therapeutic effectiveness and safety of epigenetic drugs. In this review, we focus on the mechanism and role of epigenetic regulatory factors in diseases, as well as the challenges faced by small molecule inhibitors in treatment strategies, especially the research advancements in epigenetic drug delivery systems, review and discuss the therapeutic potential and challenges of using nanotechnology to develop epigenetic drug delivery systems.

Multi-step HPLC fractionation enabled in-depth and unbiased characterization of histone PTMs

Histone post-translational modifications (PTMs) are critical epigenetic regulatory factors. Histone PTMs are highly dynamic and complicated, encompassing over 30 structurally diverse modifications across nearly 180 amino acid residues, which generated extensive information regarding histone marks. In proteomics-based characterization of histone PTMs, chemical derivatization and antibody-based affinity enrichment were frequently utilized to improve the identification depth. However, chemical derivatization suffered from the occurrence of side reactions, and antibody-based affinity enrichment focused on specific PTM types of interest. In this research, we developed a multi-step fractionation strategy for comprehensively unbiased detection of histone PTM sites. By combining protein-level fractionation with peptide-level alkaline and acid phase fractionation, we developed the Multidimensional Fractionation based Histone Mark Identification Technology (MudFIT) and increased PTM identification to a total of 264 histone PTM sites. To the best of our knowledge, this strategy achieved the most comprehensive characterization of histone PTM sites in a single proteomics study. Using the same starting amount of sample, MudFIT identified more Kac sites and Kac peptides than those in antibody-based acetylated peptide enrichment. Moreover, in addition to well-studied histone marks, we discovered 36 potential new histone PTM sites including H2BK116bu, H4R45me2, H1K63pr, and uncovered unknown histone PTM types like aminoadipic on lysine and nitrosylation on tyrosine. Our data provided a method and resource for in-depth characterization of histone PTM sites, facilitating further biological understanding of histone marks.

SGK1 promotes the lipid accumulation via regulating the transcriptional activity of FOXO1 in bovine

ObjectivesSerum/glucocorticoid-inducible kinase 1 (SGK1) gene encodes a serine/threonine protein kinase that plays an essential role in cellular stress response and regulation of multiple metabolic processes. However, its role in bovine adipogenesis remains unknown. In this study, we aimed to clarify the role of SGK1 in bovine lipid accumulation and improvement of meat quality.MethodsPreadipocytes were induced to differentiation to detect the temporal expression pattern of SGK1. Heart, liver, lung, spleen, kidney, muscle and fat tissues were collected to detect its tissue expression profile. Recombinant adenovirus and the lentivirus were packaged for overexpression and knockdown. Oil Red O staining, quantitative real-time PCR, Western blot analysis, Yeast two-hybrid assay, luciferase assay and RNA-seq were performed to study the regulatory mechanism of SGK1.ResultsSGK1 showed significantly higher expression in adipose and significantly induced expression in differentiated adipocytes. Furthermore, overexpression of SGK1 greatly promoted adipogenesis and inhibited proliferation, which could be shown by the remarkable increasement of lipid droplet, and the expression levels of adipogenic marker genes and cell cycle-related genes. Inversely, its knockdown inhibited adipogenesis and facilitated proliferation. Mechanistically, SGK1 regulates the phosphorylation and expression of two critical proteins of FoxO family, FOXO1/FOXO3. Importantly, SGK1 attenuates the transcriptional repression role of FOXO1 for PPARγ via phosphorylating the site S256, then promoting the bovine fat deposition.ConclusionsSGK1 is a required epigenetic regulatory factor for bovine preadipocyte proliferation and differentiation, which contributes to a better understanding of fat deposition and meat quality improvement in cattle.

Epigenetic insights into an epimutant colorless non-ripening: from fruit ripening to stress responses.

The epigenetic machinery has received extensive attention due to its involvement in plant growth, development, and adaptation to environmental changes. Recent studies often highlight the epigenetic regulatory network by discussing various epigenetic mutants across various plant species. However, a systemic understanding of essential epigenetic regulatory mechanisms remains limited due to a lack of representative mutants involved in multiple biological processes. Colorless Non-ripening (Cnr), a spontaneous epimutant isolated from a commercial population, was initially characterized for its role in fruit ripening regulation. Cnr fruits exhibit an immature phenotype with yellow skin, attributed to hypermethylation of the SQUAMOSA PROMOTER BINDING PROTEIN-LIKE-CNR (SlSPL-CNR) promoter, resulting in the repression of gene expression. In addition to DNA methylation, this process also involves histone modification and microRNA, integrating multiple epigenetic regulatory factors. Interestingly, knockout mutants of SlSPL-CNR display phenotypical distinctions from Cnr in fruit ripening, indicating complex genetic and epigenetic control over the non-ripening phenotype in Cnr fruits. Accumulating evidence suggests that Cnr epimutation is pleiotropic, participating in various biological processes such as Cd stress, Fe deficiency, vivipary, and cell death. Therefore, the Cnr epimutant serve as an excellent model for unveiling how epigenetic mechanisms are involved in diverse biological processes. This review paper focuses on recent research advances regarding the Cnr epimutant, delving into its complex genetic and epigenetic regulatory mechanisms, with the aim of enhancing our understanding and facilitating the development of high-quality, high-yield crops through epigenetic modification.

Pan-cancer and multi-omics analyses revealed the diagnostic and prognostic value of BAZ2A in liver cancer

BAZ2A, an epigenetic regulatory factor that affects ribosomal RNA transcription, has been shown to be highly expressed in several cancers and promotes tumor cell migration. This study explored the expression and mechanism of BAZ2A in tumorigenesis at the pan-cancer level. The Cancer Genome Atlas, Gene Expression Omnibus databases and TIMER2.0, cBioPortal and other tools were used to analyze the level of expression of BAZ2A in various tumor tissues and to examine the relationship between BAZ2A and survival, prognosis, mutation and immune invasion. In vitro experiments were performed to assess the function of BAZ2A in cancer cells. Using combined transcriptome and proteome analysis, we examined the possible mechanism of BAZ2A in tumors. BAZ2A exhibited high expression levels in multiple tumor tissues and displayed a significant association with cancer patient prognosis. The main type of BAZ2A genetic variation in cancer is gene mutation. Downregulation of BAZ2A inhibited proliferation, migration, and invasion and promoted apoptosis in LM6 liver cancer cell. The mechanism of BAZ2A in cancer development may involve lipid metabolism. These results help expand our understanding of BAZ2A in tumorigenesis and development and suggest BAZ2A may serve as a prognostic and diagnostic factor in several cancers.

Why do we age? The main signs of aging

Aging is a gradual and irreversible pathophysiological process. This is manifested in the decline of tissue and cell functions and a significant variety of pathologies associated with aging, including neurodegenerative diseases, cardiovascular diseases, metabolic disorders, increased risk of diseases of the skeleton and the immune system. Although modern medical advances have made a certain contribution to human health and greatly extended life expectancy, along with the aging of society, various chronic diseases are gradually emerging, which are the most important causes of disability and death of the elderly. Aim. The aim of the work is to analyze modern ideas in the field of causes and manifestations of aging processes for the possibility of developing a strategy to slow down its course. At the molecular and cellular level, aging is a complex biological process involving the gradual deterioration of various cellular and molecular processes in the body over time. The length of a person’s life is closely related to the decrease in the possibilities of repair and regeneration of tissues and organs. In response to stress at the molecular, cellular, and systemic levels, genetic, epigenetic, and environmental regulatory factors cause a decrease in the body’s physiological capabilities. They use complex molecular mechanisms that together contribute to aging. Molecular mechanisms (such as telomere shortening, accumulation of DNA damage, metabolic changes, and excessive free radical generation) strongly link various factors to the rate of aging. Collectively, these mechanisms inhibit cell proliferation, alter metabolism and gene expression, and induce high levels of free radicals, maintaining a senescent cell phenotype. Although the number of early senescent cells is low, they can limit the regenerative capacity of tissue stem cells and lead to the accumulation of cellular damage, thereby contributing to age-related diseases. Conclusions. Current advances in high-throughput genomics, transcriptomics, proteomics, and metabolomics enable the characterization and quantification of thousands of epigenetic markers, transcripts, proteins, metabolites, and can reveal general changes that occur with age in complex organisms at the molecular level. Thus, the integration of these molecular markers and related molecular mechanisms into a comprehensive assessment of biological age to prevent age-related functional decline and morbidity is becoming an increasingly pressing issue in medical science and should be implemented in practice as soon as possible.

Epigenetic regulatory differentiation of hematopoietic stem cells to the red lineage Running head: Epigenetics of erythropoiesis

The differentiation process from hematopoietic (HSCs) to mature red blood cells (RBCs) is characterized by remarkable precision and is tightly controlled from the initial lineage commitment to eventual terminal differentiation. Erythropoiesis is the dynamic journey of HSCs through various functional and phenotypic stages. The physiological course of erythrogenesis is intricately linked to significant changes in chromatin accessibility, necessitating precise coordination of transcription factors and epigenetic elements. This review presents a comprehensive overview of recent investigations into the molecular-level epigenetic regulatory factors that influence differentiation of the erythroid lineage. This encompasses the exploration of transcriptional, post-transcriptional, and post-translational regulatory processes. The intricate interplay of epigenetic and transcriptional regulatory networks in erythroid differentiation not only enhances our understanding of this fundamental biological process, but also provides valuable insights into the underlying mechanisms contributing to the pathogenesis of disorders associated with abnormal erythroid development. These findings hold significant promise for the development of novel therapeutic strategies to address these diseases and improve patient outcomes.

The roles of chromatin regulatory factors in endometriosis.

Endometriosis is an estrogen-dependent inflammatory disease and one of the most common gynecological diseases in women of reproductive age. The aim of the review was to explore the relationship between the chromatin regulatory factors and endometriosis. By searching for literature on chromatin regulators and endometriosis in PuMed. Finally, 98 documents were selected. Chromatin regulators (CRs) are essential epigenetic regulatory factors that can regulate chromatin structure changes and are usually divided into three categories: DNA methylation compounds, histone modification compounds, and chromatin remodeling complexes. Noncoding RNAs are also chromatin regulators and can form heterochromatin by binding to protein complexes. Chromatin regulators cause abnormal gene expression by regulating chromatin structure, thereby affecting the occurrence and development of endometriosis. This review summarizes the participation of chromatin regulators in the mechanisms of endometriosis, and these changes in related chromatin regulators provide a comprehensive reference for diagnosis and treatment of endometriosis.

Unveiling the imprinted dance: how parental genomes orchestrate seed development and hybrid success.

Parental epigenetic asymmetries, which contribute to the monoallelic expression of genes known as imprints, play a critical role in seed development in flowering plants. Primarily, differential DNA methylation patterns and histone modifications on parental alleles form the molecular basis of gene imprinting. Plants predominantly exhibit this non-Mendelian inheritance phenomenon in the endosperm and the early embryo of developing seeds. Imprinting is crucial for regulating nutrient allocation, maintaining seed development, resolving parental conflict, and facilitating evolutionary adaptation. Disruptions in imprinted gene expression, mediated by epigenetic regulators and parental ploidy levels, can lead to endosperm-based hybridization barriers and hybrid dysfunction, ultimately reducing genetic diversity in plant populations. Conversely, imprinting helps maintain genetic stability within plant populations. Imprinted genes likely influence seed development in various ways, including ensuring proper endosperm development, influencing seed dormancy, and regulating seed size. However, the functions of most imprinted genes, the evolutionary significance of imprinting, and the long-term consequences of imprinting disruptions on plant development and adaptation need further exploration. Thus, it is clear that research on imprinting has immense potential for improving our understanding of plant development and ultimately enhancing key agronomic traits. This review decodes the possible genetic and epigenetic regulatory factors underpinning genomic imprinting and their positive and negative consequences on seed development. This study also forecasts the potential implications of exploiting gene imprinting for crop improvement programs.

Survival Outcomes Associated with Molecular and Cytogenetic Alterations in AML Patients Treated with Hypomethylating Agent and Venetoclax

Molecular profiling has improved prognostication and helped identify novel therapeutic targets in AML. Nonetheless, it has also created a complex web of molecular profiles and cytogenetic abnormalities and in many cases it remains unclear which specific alterations primarily drive leukemogenesis. We sought to review our patients (pts) treated with a hypomethylating agent (HMA) + Venetoclax (Ven), to evaluate molecular and cytogenetic profiles with their associated outcomes. We identified 142 pts with AML treated with HMA + Ven at Northwell Health between January 2019 and December 2023. Through retrospective chart review, we obtained patient and disease characteristics, treatment regimens, clinical outcomes as well as molecular and cytogenetic profiling (using commercial AML panels) prior to the initiation of HMA + Ven. Bone marrow biopsy pathology reports were reviewed to identify the subtype of AML and grouped into De novo AML, AML with MDS related changes (AML-MRC) and therapy-related AML (t-AML). Median relapse free survival (mRFS) and median overall survival (mOS) in months (m) as defined by ELN 2022 (Dohner et al, Blood 2022), were estimated with Kaplan-Meier curves and compared utilizing log-rank testing. T-test was used to evaluate significant differences between categorical data. Of the 142 pts identified, the median age was 77. The majority of patients had adverse (n = 99) or intermediate risk (n = 31) genetics as defined by the 2022 ELN genetic risk classification. The overall response rate (ORR) was 42% with mOS of 9.6m. AML-MRC patients (n=80) had mOS of 9.1m and mRFS of 11.6m with 61 pts receiving HMA + Ven as frontline treatment. 47 pts with De novo AML had mOS of 13.4m and mRFS of 16.1m with 36 pts receiving HMA + Ven as frontline therapy. Only 15 pts had t-AML with mRFS of 12.3m and mOS of 8.8m with 10 pts receiving HMA + Ven as frontline therapy. There was no significant difference in mRFS or mOS between these groups, although there was a trend favoring De novo AML. 47 different molecular alterations were identified among the 142 patients. Figure 1 illustrates outcomes associated with the 16 most prevalent molecular alterations found in our AML population. Mutational burden was similar between AML types (2.7 vs 3.0 vs 2.4 mutations per pt). De novo AML was associated with an increased mutation burden in signaling molecules (60%) and transcription factors (47%) compared to AML-MRC (29%, 31%). AML-MRC had a higher occurrence of mutations in epigenetic regulatory genes (79%) and splicing factors (31%) compared to De novo AML (55%, 19%). Mutations in splicing factors were associated with a significant increase in both mRFS and mOS(p = 0.01) compared to pts without mutations. Pts with DNMT3A, NPM1 or SRSF2 mutations had the highest ORR to HMA + Ven (63%, 64% and 63% respectively). RUNX1, TP53, complex cytogenetics and del 7q were associated with worse ORR (46%, 36%, 46% and 42% respectively) as well as decreased mOS. SRSF2, mutated in both AML-MRC and De novo AML, not only had an elevated ORR, but improved mRFS and mOS. Contrarily, mRFS and mOS were not significantly improved despite the high ORR in DMT3A mutated pts. DNMT3A was mutated most often in AML-MRC and was associated with a higher rate of other epigenetic regulatory gene co-mutations. The same is true for patients with KMT2A mutations (ORR 50%, mOS 2.8m, mRFS 6.1m) which suggests ineffectiveness of HMA+ Ven in maintaining remissions with this alteration with possible early selection for resistant clones. RUNX1 mutations were associated with an improved mRFS (16.1m) despite lower mOS (8.8m). NPM1 mutations had the highest mRFS of 34.4m. The survival advantage may be secondary to the absence of adverse cytogenetics in 88% of these pts. IDH2 mutations was associated with a significantly improved mOS compared to unmutated IDH2; however this may be confounded by the use of an IDH2 inhibitor at relapse. Our review of molecular alterations in AML pts identified several molecular alterations such as SRSF2, DNMT3A, RUNX1 which we found to be associated with favorable responses when treated with HMA + Ven. In addition, we demonstrated that NPM1 mutation remains favorable in patients treated with HMA + Ven. Our findings help contribute to the ever-growing, complex molecular and genomic profiling of AML patients.

Phenotypic and genomic changes during Turnip mosaic virus adaptation to Arabidopsis thaliana mutants lacking epigenetic regulatory factors.

In this study, we investigated how an emerging RNA virus evolves, interacts, and adapts to populations of a novel host species with defects in epigenetically controlled plant defense mechanisms. Mutations in epigenetic regulatory pathways would exert different effects on defense-response genes but also induce large-scale alterations in cellular physiology and homeostasis. To test whether these effects condition the emergence and subsequent adaptation of a viral pathogen, we have evolved five independent lineages of a naive turnip mosaic virus (TuMV) strain in a set of Arabidopsis thaliana genotypes carrying mutations that influence important elements of two main epigenetic pathways and compare the results with those obtained for viral lineages evolved in wild-type plants. All evolved lineages showed adaptation to the lack of epigenetically regulated responses through significant increases in infectivity, virulence, and viral load although the magnitude of the improvements strongly depended on the plant genotype. In early passages, these traits evolved more rapidly, but the rate of evolution flattened out in later ones. Viral load was positively correlated with different measures of virulence, though the strength of the associations changed from the ancestral to the evolved viruses. High-throughput sequencing was used to evaluate the viral diversity of each lineage, as well as characterizing the nature of fixed mutations, evolutionary convergences, and potential targets of TuMV adaptation. Within each lineage, we observed a net increase in genome-wide genetic diversity, with some instances where nonsynonymous alleles experienced a transient rise in abundance before being displaced by the ancestral allele. In agreement with previous studies, viral VPg protein has been shown as a key player in the adaptation process, even though no obvious association between fixed alleles and host genotype was found.

Involvement of CCCTC-binding factor in epigenetic regulation of cancer.

A major global health burden continues to be borne by the complex and multifaceted disease of cancer. Epigenetic changes, which are essential for the emergence and spread of cancer, have drawn a huge amount of attention recently. The CCCTC-binding factor (CTCF), which takes part in a wide range of cellular processes including genomic imprinting, X chromosome inactivation, 3D chromatin architecture, local modifications of histone, and RNA polymerase II-mediated gene transcription, stands out among the diverse array of epigenetic regulators. CTCF not only functions as an architectural protein but also modulates DNA methylation and histone modifications. Epigenetic regulation of cancer has already been the focus of plenty of studies. Understanding the role of CTCF in the cancer epigenetic landscape may lead to the development of novel targeted therapeutic strategies for cancer. CTCF has already earned its status as a tumor suppressor gene by acting like a homeostatic regulator of genome integrity and function. Moreover, CTCF has a direct effect on many important transcriptional regulators that control the cell cycle, apoptosis, senescence, and differentiation. As we learn more about CTCF-mediated epigenetic modifications and transcriptional regulations, the possibility of utilizing CTCF as a diagnostic marker and therapeutic target for cancer will also increase. Thus, the current review intends to promote personalized and precision-based therapeutics for cancer patients by shedding light on the complex interplay between CTCF and epigenetic processes.

Ribosomal S6 protein kinase 4 promotes resistance to EZH2 inhibitors in glioblastoma.

Glioblastoma (GBM) is a highly malignant type of brain tumor with limited treatment options. Recent research has focused on epigenetic regulatory factors, such as Enhancer of Zeste Homolog 2 (EZH2), which plays a role in gene expression through epigenetic modifications. EZH2 inhibitors have been developed as potential therapeutic agents for GBM, but resistance to these inhibitors remains a considerable challenge. This study aimed to investigate the role of ribosomal S6 protein kinase 4 (RSK4) in GBM and its association with resistance to EZH2 inhibitors. We first induced drug resistance in primary GBM cell lines by treatment with an EZH2 inhibitor and observed increases in the expression of stemness markers associated with glioblastoma stem cells (GSCs) in the drug-resistant cells. We also found high expression of RSK4 in GBM patient samples and identified the correlation of high RSK4 expression with poor prognosis and GSC marker expression. Further experiments showed that knocking down RSK4 in drug-resistant GBM cells restored their sensitivity to EZH2 inhibitors and decreased the expression of GSC markers, thus reducing their self-renewal capacity. From a mechanistic perspective, we discovered that RSK4 directly phosphorylates EZH2, activating the EZH2/STAT3 pathway and promoting resistance to EZH2 inhibitors in GBM. We also found that combining EZH2 inhibitors with an RSK4 inhibitor called BI-D1870 had better inhibitory effects on GBM occurrence and progression in both in vitro and in vivo experiments. In conclusion, this study demonstrates that RSK4 enhances cancer stemness and mediates resistance to EZH2 inhibitors in GBM. Combination treatment with EZH2 inhibitors and RSK4 inhibitors is a promising potential therapeutic strategy for GBM. Collectively, our results strongly demonstrate that RSK4 regulates the EZH2/STAT3 pathway to promote GSC maintenance and EZH2i resistance in a PRC2-independent manner, indicating that RSK4 is a promising therapeutic target for GBM.

The activation of histone deacetylases 4 prevented endothelial dysfunction: A crucial mechanism of HuangqiGuizhiWuwu Decoction in improving microcirculation dysfunction in diabetes.

The regulation of epigenetic factors is considered a crucial target for solving complex chronic diseases such as cardio-cerebrovascular diseases. HuangqiGuizhiWuwu Decoction (HGWWD), a classic Chinese prescription, is mainly used to treat various vascular diseases. Although our previous studies reported that HGWWD could effectively prevent vascular dysfunction in diabetic rodent models, the precise mechanism is still elusive. In this study, we investigated the epigenetic mechanisms of modulating the damage of vascular endothelial cells in diabetes by HGWWD. We first analyzed common active components of HGWWD by using HPLC-Q-TOF-MS/MS analysis, and predicted the isoforms of histone deacetylase (HDAC) that can potentially combine the above active components by systems pharmacology. Next, we screened the involvement of specific HDAC isoforms in the protective effect of HGWWD on vascular injury by using pharmacological blockade combined with the evaluation of vascular function in vivo and in vitro. Firstly, HDAC1, HDAC2, HDAC3, HDAC4, HDAC6, HDAC7, SIRT2, and SIRT3 have been implicated with the possibility of binding to the thirty-one common active components in HGWWD. Furthermore, the protective effect of HGWWD is reversed by both TSA (HDAC inhibitor) and MC1568 (class II HDAC inhibitor) on vascular impairment accompanied by reduced aortic HDAC activity in STZ mice. Finally, inhibition of HDAC4 blocked the protective effect of HGWWD on microvascular and endothelial dysfunction in diabetic mice. These results prove the key role of HDAC4 in diabetes-induced microvascular dysfunction and underlying epigenetic mechanisms for the protective effect of HGWWD in diabetes.

PAH Pathogenic Variants and Clinical Correlations in a Group of Hyperphenylalaninemia Patients from North-Western Romania.

Phenylketonuria (PKU) is caused by mutations in the phenylalanine hydroxylase (PAH) gene and is characterized by altered amino acid metabolism. More than 1500 known PAH variants intricately determine a spectrum of metabolic phenotypes. We aim to report on clinical presentation and PAH variants identified in 23 hyperphenylalaninemia (HPA)/PKU Romanian patients. Our cohort exhibited classic PKU (73.9%, 17/23), mild PKU (17.4%, 4/23), and mild HPA (8.7%, 2/23). Severe central nervous system sequelae are frequent in our cohort in late-diagnosis symptomatic patients, which highlights yet again the significance of an early dietary treatment, neonatal screening and diagnosis, and facilitated access to treatment. Next-generation sequencing (NGS) identified a total of 11 PAH pathogenic variants, all previously reported, mostly missense changes (7/11) in important catalytic domains. c.1222C>T p.Arg408Trp was the most frequent variant, with an allele frequency of 56.5%. Twelve distinct genotypes were identified, the most frequent of which was p.Arg408Trp/p.Arg408Trp (34.8%, 8/23). Compound heterozygous genotypes were common (13/23), three of which had not been previously reported to the best of our knowledge; two correlated with cPKU and one showed an mPKU phenotype. Generally, there are genotype-phenotype correlation overlaps with the public data reported in BIOPKUdb; as our study shows, clinical correlates are subject to variation, in part due to uncontrolled or unknown epigenetic or environmental regulatory factors. We highlight the importance of establishing the genotype on top of using blood phenylalanine levels.

The relationship between residential exposure to atmospheric pollution and circulating miRNA in adults living in an urban area in northern France

IntroductionMicroRNAs are epigenetic regulatory factors capable of silencing the expression of target genes and might mediate the effects of air pollution on health. The objective of the present population-based study was to investigate the association between microRNA expression and long-term, residential exposure to atmospheric PM10 and NO2. MethodWe included 998 non-smoking adult participants from the cross-sectional ELISABET survey (2010–2014) in the Lille urban area of France. The mean residential annual pollution levels were estimated with an atmospheric dispersion modelling system. Ten microRNAs were selected on the basis of the literature data, together with two housekeeping microRNAs (miR-93-5p and miR-191-5p) and were quantified with RT-qPCRs. Multivariate linear regression models were used to study the association between microRNAs and air pollution. The threshold for statistical significance (after correction for the FDR) was set to p < 0.1. ResultsThe mean annual exposure between 2011 and the year of inclusion was 26.4 ± 2.0 µg/m3 for PM10 and 24.7 ± 5.1 µg/m3 for NO2. Each 2 µg/m3 increment in PM10 exposure was associated with an 8.6% increment (95%CI [3.1; 14.3]; pFDR = 0.019) in miR-451a expression.A 5 µg/m3 increment in NO2 exposure was associated with a 5.3% increment ([0.7; 10]; pFDR = 0.056) in miR451a expression, a 3.6% decrement (95%CI [-6.1; −1.1]; pFDR = 0.052) in miR-223-3p expression, a 3.8% decrement (95%CI[-6.8; −0.7]; pFDR = 0.079) in miR-28-3p expression, a 4.3% decrement (95%CI [-7.7; −0.8]; pFDR = 0.055) in miR-146a-5p expression, and a 4.0% decrement (95% CI[−7.4; −0.4]; pFDR = 0.059) in miR-23a-5p expression. The difference between the two housekeeping microRNAs miR-93-5p and miR-191-5p was also associated with PM10 and NO2 exposure. ConclusionOur results suggest that circulating miRNAs are potentially valuable biomarkers of the effects of air pollution.

Transcriptional regulation of macrophages in heart failure.

Adverse cardiac remodeling after acute myocardial infarction is the most important pathological mechanism of heart failure and remains a major problem in clinical practice. Cardiac macrophages, derived from tissue resident macrophages and circulating monocyte, undergo significant phenotypic and functional changes following cardiac injury and play crucial roles in inflammatory response and tissue repair response. Currently, numerous studies indicate that epigenetic regulatory factors and transcription factors can regulate the transcription of inflammatory and reparative genes and timely conversion of inflammatory macrophages into reparative macrophages and then alleviate cardiac remodeling. Accordingly, targeting transcriptional regulation of macrophages may be a promising option for heart failure treatment. In this review, we not only summarize the origin and function of cardiac macrophages, but more importantly, describe the transcriptional regulation of macrophages in heart failure, aiming to provide a potential therapeutic target for heart failure.

The Transcription Factor NRF2 Has Epigenetic Regulatory Functions Modulating HDACs, DNMTs, and miRNA Biogenesis.

The epigenetic regulation of gene expression is a complex and tightly regulated process that defines cellular identity and is associated with health and disease processes. Oxidative stress is capable of inducing epigenetic modifications. The transcription factor NRF2 (nuclear factor erythroid-derived 2-like 2) is a master regulator of cellular homeostasis, regulating genes bearing antioxidant response elements (AREs) in their promoters. Here, we report the identification of ARE sequences in the promoter regions of genes encoding several epigenetic regulatory factors, such as histone deacetylases (HDACs), DNA methyltransferases (DNMTs), and proteins involved in microRNA biogenesis. In this research, we study this possibility by integrating bioinformatic, genetic, pharmacological, and molecular approaches. We found ARE sequences in the promoter regions of genes encoding several HDACs, DNMTs, and proteins involved in miRNA biogenesis. We confirmed that NRF2 regulates the production of these genes by studying NRF2-deficient cells and cells treated with dimethyl fumarate (DMF), an inducer of the NRF2 signaling pathway. In addition, we found that NRF2 could be involved in the target RNA-dependent microRNA degradation (TDMD) of miR-155-5p through its interaction with Nfe2l2 mRNA. Our data indicate that NRF2 has an epigenetic regulatory function, complementing its traditional function and expanding the regulatory dimensions that should be considered when developing NRF2-centered therapeutic strategies.

Topological implications of DNA tumor viral episomes

A persistent DNA tumor virus infection transforms normal cells into cancer cells by either integrating its genome into host chromosomes or retaining it as an extrachromosomal entity called episome. Viruses have evolved mechanisms for attaching episomes to infected host cell chromatin to efficiently segregate the viral genome during mitosis. It has been reported that viral episome can affect the gene expression of the host chromosomes through interactions between viral episomes and epigenetic regulatory host factors. This mini review summarizes our current knowledge of the tethering sites of viral episomes, such as EBV, KSHV, and HBV, on host chromosomes analyzed by three-dimensional genomic tools. [BMB Reports 2022; 55(12): 587-594].