Updates of precision medicine in type 2 diabetes

Diabetes mellitus is prevalent worldwide and affects 1 in 10 adults. Despite the successful development of glucose-lowering drugs, such as glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 inhibitors recently, the proportion of patients achieving satisfactory glucose control has not risen as expected. The heterogeneity of diabetes determines that a one-size-fits-all strategy is not suitable for people with diabetes. Diabetes is undoubtedly more heterogeneous than the conventional subclassification, such as type 1, type 2, monogenic and gestational diabetes. The recent progress in genetics and epigenetics of diabetes has gradually unveiled the mechanisms underlying the heterogeneity of diabetes, and cluster analysis has shown promising results in the substratification of type 2 diabetes, which accounts for 95% of diabetic patients. More recently, the rapid development of sophisticated glucose monitoring and artificial intelligence technologies further enabled comprehensive consideration of the complex individual genetic and clinical information and might ultimately realize a precision diagnosis and treatment in diabetics.

Enhancer deregulation inTET2-mutant clonal hematopoiesis is associated with increased COVID-19 severity and mortality

Background: COVID-19 causes significant morbidity and mortality, albeit with considerable heterogeneity among affected individuals. It remains unclear which host factors determine disease severity and survival. Given the propensity of clonal hematopoiesis (CH) to promote inflammation in healthy individuals, we investigated its effect on COVID-19 outcomes. Method(s): We performed a multi-omics interrogation of the genome, epigenome, transcriptome, and proteome of peripheral blood mononuclear cells from COVID-19 patients (n=227). We obtained clinical data, laboratory studies, and survival outcomes. We determined CH status and TET2-related DNA methylation. We performed single-cell proteogenomics to understand clonal composition in relation to cell phenotype. We interrogated single-cell gene expression in isolation and in conjunction with DNA accessibility. We integrated these multi-omics data to understand the effect of CH on clonal composition, gene expression, methylation of cis-regulatory elements, and lineage commitment in COVID-19 patients. We performed shRNA knockdowns to validate the effect of one candidate transcription factor in myeloid cell lines. Result(s): The presence of CH was strongly associated with COVID-19 severity and all-cause mortality, independent of age (HR 3.48, 95% CI 1.45-8.36, p=0.005). Differential methylation of promoters and enhancers was prevalent in TET2-mutant, but not DNMT3A-mutant CH. TET2- mutant CH was associated with enhanced classical/intermediate monocytosis and single-cell proteogenomics confirmed an enrichment of TET2 mutations in these cell types. We identified celltype specific gene expression changes associated with TET2 mutations in 102,072 single cells (n=34). Single-cell RNA-seq confirmed the skewing of hematopoiesis towards classical and intermediate monocytes and demonstrated the downregulation of EGR1 (a transcription factor important for monocyte differentiation) along with up-regulation of the lncRNA MALAT1 in monocytes. Combined scRNA-/scATAC-seq in 43,160 single cells (n=18) confirmed the skewing of hematopoiesis and up-regulation of MALAT1 in monocytes along with decreased accessibility of EGR1 motifs in known cis-regulatory elements. Using myeloid cell lines for functional validation, shRNA knockdowns of EGR1 confirmed the up-regulation of MALAT1 (in comparison to wildtype controls). Conclusion(s): CH is an independent prognostic factor in COVID-19 and skews hematopoiesis towards monocytosis. TET2-mutant CH is characterized by differential methylation and accessibility of enhancers binding myeloid transcriptions factors including EGR1. The ensuing loss of EGR1 expression in monocytes causes MALAT1 overexpression, a factor known to promote monocyte differentiation and inflammation. These data provide a mechanistic insight to the adverse prognostic impact of CH in COVID-19.

Comprehensive DNA methylation profiling of COVID-19 and hepatocellular carcinoma to identify common pathogenesis and potential therapeutic targets.

BACKGROUND & AIMS: The effects of SARS-CoV-2 infection can be more complex and severe in patients with hepatocellular carcinoma (HCC) as compared to other cancers. This is due to several factors, including pre-existing conditions such as viral hepatitis and cirrhosis, which are commonly associated with HCC. METHODS: We conducted an analysis of epigenomics in SARS-CoV-2 infection and HCC patients, and identified common pathogenic mechanisms using weighted gene co-expression network analysis (WGCNA) and other analyses. Hub genes were identified and analyzed using LASSO regression. Additionally, drug candidates and their binding modes to key macromolecular targets of COVID-19 were identified using molecular docking. RESULTS: The epigenomic analysis of the relationship between SARS-CoV-2 infection and HCC patients revealed that the co-pathogenesis was closely linked to immune response, particularly T cell differentiation, regulation of T cell activation and monocyte differentiation. Further analysis indicated that CD4+ T cells and monocytes play essential roles in the immunoreaction triggered by both conditions. The expression levels of hub genes MYLK2, FAM83D, STC2, CCDC112, EPHX4 and MMP1 were strongly correlated with SARS-CoV-2 infection and the prognosis of HCC patients. In our study, mefloquine and thioridazine were identified as potential therapeutic agents for COVID-19 in combined with HCC. CONCLUSIONS: In this research, we conducted an epigenomics analysis to identify common pathogenetic processes between SARS-CoV-2 infection and HCC patients, providing new insights into the pathogenesis and treatment of HCC patients infected with SARS-CoV-2.

An epigenetic synopsis of parental substance use.

The rate of substance use is rising, especially among reproductive-age individuals. Emerging evidence suggests that paternal pre-conception and maternal prenatal substance use may alter offspring epigenetic regulation (changes to gene expression without modifying DNA) and outcomes later in life, including neurodevelopment and mental health. However, relatively little is known due to the complexities and limitations of existing studies, making causal interpretations challenging. This review examines the contributions and influence of parental substance use on the gametes and potential transmissibility to the offspring's epigenome as possible areas to target public health warnings and healthcare provider counseling of individuals or couples in the pre-conception and prenatal periods to ultimately mitigate short- and long-term offspring morbidity and mortality.

More people, especially those of reproductive age, are using substances, and there is growing evidence to suggest that parental substance use before and during pregnancy may adversely affect offspring and result in issues later in life, including mental health challenges. Such relationships have been demonstrated with nicotine, alcohol, cannabis, opioids and illegal drugs (e.g., heroin, cocaine, methamphetamines). Some of these adverse impacts on offspring can potentially be passed down in families even after parents have quit using the substance. Because more individuals are using drugs, especially during the COVID-19 pandemic, it is important that families learn more about the potential impact of substance use on their future offspring before they try to get pregnant.

Computer-aided comprehensive explorations of RNA structural polymorphism through complementary simulation methods

While RNA folding was originally seen as a simple problem to solve, it has been shown that the promiscuous interactions of the nucleobases result in structural polymorphism, with several competing structures generally observed for non-coding RNA. This inherent complexity limits our understanding of these molecules from experiments alone, and computational methods are commonly used to study RNA. Here, we discuss three advanced sampling schemes, namely Hamiltonian-replica exchange molecular dynamics (MD), ratchet-and-pawl MD and discrete path sampling, as well as the HiRE-RNA coarse-graining scheme, and highlight how these approaches are complementary with reference to recent case studies. While all computational methods have their shortcomings, the plurality of simulation methods leads to a better understanding of experimental findings and can inform and guide experimental work on RNA polymorphism.Copyright ©

Relationship between cognitive dysfunction and the promoter methylation of PER1 and CRY1 in patients with cerebral small vessel disease.

Background and purpose: The prevalence of cerebral small vessel disease (CSVD) is increasing due to the accelerating global aging process, resulting in a substantial burden on all countries, as cognitive dysfunction associated with CSVD is also on the rise. Clock genes have a significant impact on cognitive decline and dementia. Furthermore, the pattern of DNA methylation in clock genes is strongly associated with cognitive impairment. Thus, the aim of this study was to explore the connection between DNA promoter methylation of PER1 and CRY1 and cognitive dysfunction in patients with CSVD. Methods: We recruited patients with CSVD admitted to the Geriatrics Department of the Lianyungang Second People's Hospital between March 2021 and June 2022. Based on their Mini-Mental State Examination score, patients were categorized into two groups: 65 cases with cognitive dysfunction and 36 cases with normal cognitive function. Clinical data, 24-h ambulatory blood pressure monitoring parameters, and CSVD total load scores were collected. Moreover, we employed methylation-specific PCR to analyze the peripheral blood promoter methylation levels of clock genes PER1 and CRY1 in all CSVD patients who were enrolled. Finally, we used binary logistic regression models to assess the association between the promoter methylation of clock genes (PER1 and CRY1) and cognitive dysfunction in patients with CSVD. Results: (1) A total of 101 individuals with CSVD were included in this study. There were no statistical differences between the two groups in baseline clinical data except MMSE and AD8 scores. (2) After B/H correction, the promoter methylation rate of PER1 was higher in the cognitive dysfunction group than that in the normal group, and the difference was statistically significant (adjusted p < 0.001). (3) There was no significant correlation between the promoter methylation rates of PER1 and CRY1 in peripheral blood and circadian rhythm of blood pressure (p > 0.05). (4) Binary logistic regression models showed that the influence of promoter methylation of PER1 and CRY1 on cognitive dysfunction were statistically significant in Model 1 (p < 0.001; p = 0.025), and it still existed after adjusting for confounding factors in Model 2. Patients with the promoter methylation of PER1 gene (OR = 16.565, 95%CI, 4.057-67.628; p < 0.001) and the promoter methylation of CRY1 gene (OR = 6.017, 95%CI, 1.290-28.069; p = 0.022) were at greater risk of cognitive dysfunction compared with those with unmethylated promoters of corresponding genes in Model 2. Conclusion: The promoter methylation rate of PER1 gene was higher in the cognitive dysfunction group among CSVD patients. And the hypermethylation of the promoters of clock genes PER1 and CRY1 may be involved in affecting cognitive dysfunction in patients with CSVD.

Pilot study suggests DNA methylation of the glucocorticoid receptor gene (NR3C1) is associated with MDMA-assisted therapy treatment response for severe PTSD.

Background: Previous research has demonstrated that epigenetic changes in specific hypothalamic-pituitary-adrenal (HPA) genes may predict successful psychotherapy in post-traumatic stress disorder (PTSD). A recent Phase 3 clinical trial reported high efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for treating patients with severe PTSD compared to a therapy with placebo group (NCT03537014). This raises important questions regarding potential mechanisms of MDMA-assisted therapy. In the present study, we examined epigenetic changes in three key HPA axis genes before and after MDMA and placebo with therapy. As a pilot sub-study to the parent clinical trial, we assessed potential HPA epigenetic predictors for treatment response with genomic DNA derived from saliva (MDMA, n = 16; placebo, n = 7). Methylation levels at all 259 CpG sites annotated to three HPA genes (CRHR1, FKBP5, and NR3C1) were assessed in relation to treatment response as measured by the Clinician-Administered PTSD Scale (CAPS-5; Total Severity Score). Second, group (MDMA vs. placebo) differences in methylation change were assessed for sites that predicted treatment response. Results: Methylation change across groups significantly predicted symptom reduction on 37 of 259 CpG sites tested, with two sites surviving false discovery rate (FDR) correction. Further, the MDMA-treatment group showed more methylation change compared to placebo on one site of the NR3C1 gene. Conclusion: The findings of this study suggest that therapy-related PTSD symptom improvements may be related to DNA methylation changes in HPA genes and such changes may be greater in those receiving MDMA-assisted therapy. These findings can be used to generate hypothesis driven analyses for future studies with larger cohorts.

The suppressor of cytokine signaling-1 (SOCS1) gene polymorphism and promoter methylation correlate with the course of COVID-19.

The suppressor of the cytokine signaling-1 (SOCS1) gene is a short sequence located on chromosome 16 that functions to induce an appropriate immune response and is an essential physiological regulator of interferon (IFN) signaling. In addition to comparing the global DNA and SOCS1 gene promoter methylation status between our patients with coronavirus disease 2019 (COVID-19) and healthy controls, this study demonstrates the effect of the SOCS1 rs33989964 polymorphism on patients with COVID-19. The study group included 139 patients diagnosed with COVID-19 in our hospital's clinics between June and December 2020, and the control group included 78 healthy individuals. After comparing the initial gene polymorphisms of the patients with the healthy control group, three separate clinical subgroups were formed. The gene polymorphism distribution and the methylation status of SOCS1 were examined in these clinical subgroups. Hypomethylation of the SOCS1 gene was observed in the COVID-19 patient group compared to the healthy control group (p = 0.001). Between the patients divided into two separate clinical subgroups, those with severe and mild infections, the Del/Del genotype of the SOCS1 gene was more common in patients with severe infection than in patients with mild infection (p = 0.018). Patients with the CA/CA and CA/Del genotypes were 0.201 times more likely to have a severe infection (95% CI: 0.057-0.716, p = 0.007). Having a non-Del/Del genotype was a protective factor against severe infection. The effect of the SOCS1 rs33989964 polymorphism and methylation status of the SOCS1 gene throughout the COVID-19 pandemic could be significant contributions to the literature.

Epigenetic features, methods, and implementations associated with COVID-19

The infection and life cycle of severe acute respiratory syndrome coronavirus 2 are widely studied, yet multiple gaps exist in the knowledge that affects therapeutic developments against coronavirus disease 2019 (COVID-19). Predominantly caused by a respiratory virus, COVID-19 is not restricted to the respiratory tract but affects multiple organs of the body including the cardiovascular, neurological, immunological, and renal systems. COVID-19 affects all age groups, although the elderly population inherently presenting with multiple comorbidities are disproportionately affected. The majority of the patients experience mild symptoms, although moderate, severe, and critical symptoms occur in a smaller group of patients. Interestingly, the effects of the disease can be acute or chronic and present an ongoing health care challenge. Epigenetic mechanisms of COVID-19 (DNA methylation, histone posttranslational modifications, histone citrullination, etc.) are an emerging field and present enormous potential toward the medical management of COVID-19. Angiotensin converting enzyme 2, an important protein in the cardiovascular system, is a receptor for viral entry into cells, and the epigenetic processes that regulate this protein have been widely studied. Identification of the epitranscriptomic profile has led to the identification of putative biomarkers for disease diagnosis and trials of novel epidrugs for targeted therapy. © 2023 Elsevier Inc. All rights reserved.

Maternal and Infant Outcomes Following Maternal Exposure to SARS-CoV-2 During Pregnancy in an Australian Cohort

Background: Infections during pregnancy can increase the risk for neurodevelopmental disorders in offspring. This study aimed to prospectively monitor children exposed in utero to SARS-CoV-2 from birth to 15 years of age with a secondary aim to identify biomarkers of neurodevelopmental impairments. Method(s): Women infected with SARS-CoV-2 during pregnancy and sociodemographic and age matched non-exposed women were recruited from Monash Health, Australia (N=112 mother-infant dyads). Demographics, biospecimens and clinical data are collected at multiple time points from birth-15 years using standardised sample collection and neurological and behavioural scales. We present here the birth data. Result(s): Mother-infant dyads are classified as;non-exposed, mild SARS-CoV-2 (limitation of activities) and severe SARS-CoV-2 (hospitalised). Edinburgh postnatal depression scale scores were significantly higher in severe SARS-CoV-2 vs. non-exposed mothers (p<0.05). Maternal attachment scores were unchanged. Hammersmith neonatal neurological assessment scores were unchanged across groups, as were anthropometric measures. Severe SARS-CoV-2 exposed infants had lower scores on the sensory profile 2 questionnaire auditory domain than non-exposed infants (p<0.05). Analysis of infant buccal DNA (Illumina MethylationEPIC BeadChip >850,000 CpGs, N=8) showed hypomethylation of the gene AFAP-1 (q value<0.0008), and hypermethylation of neurodevelopmental pathways;'dendrite morphology' and 'axogenesis' in SARS-CoV-2 infants vs. non-exposed. Conclusion(s): While most assessments show no group differences thus far, the severe SARS-CoV-2 exposed group are faring worse in terms of maternal mental health, infant auditory domains and infant hypermethylation of genes belonging to neurodevelopmental pathways. Follow up assessments at 1-15 years will inform as to whether these initial group differences are early signs of more severe neurodevelopmental outcomes. Funding Source: Other - One in Five Philanthropic organisation Keywords: SARS-CoV-2, Pregnancy, DNA methylation, in utero, Neurodevelopmental trajectoriesCopyright © 2023

Exploring m6A-RNA methylation as a potential therapeutic strategy for acute lung injury and acute respiratory distress syndrome.

N6-methyladenosine (m6A) is the most common methylation modification in mammalian messenger RNA (mRNA) and noncoding RNAs. m6A modification plays a role in the regulation of gene expression and deregulation of m6A methylation has been implicated in many human diseases. Recent publications suggest that exploitation of this methylation process may possess utility against acute lung injury (ALI). ALI and its more severe form, acute respiratory distress syndrome (ARDS) are acute, inflammatory clinical syndromes characterized by poor oxygenation and diffuse pulmonary infiltrates. This syndrome is associated with microvascular endothelial dysfunction, subsequent pulmonary hypertension and may ultimately lead to mortality without rigorous and acute clinical intervention. Over the years, many attempts have been made to detect novel therapeutic avenues for research without much success. The urgency for the discovery of novel therapeutic agents has become more pronounced recently given the current pandemic infection of coronavirus disease 2019 (COVID-2019), still ongoing at the time that this review is being written. We review the current landscape of literature regarding ALI and ARDS etiology, pathophysiology, and therapeutics and present a potential role of m6A methylation. Additionally, we will establish the axiomatic principles of m6A methylation to provide a framework. In conclusion, METTL3, or methyltransferase-like 3, the selective RNA methyltransferase for m6A, is a hub of proinflammatory gene expression regulation in ALI, and using a modern drug discovery strategy will identify new and effective ALI drug candidates targeting METTTL3.

Image Scanning Microscopy to Investigate Polycomb Protein Colocalization onto Chromatin

Super-resolution microscopy has been recently applied to understand the 3D topology of chromatin at an intermediated genomic scale (kilobases to a few megabases), as this corresponds to a sub-diffraction spatial scale crucial for the regulation of gene transcription. In this context, polycomb proteins are very renowned gene repressors that organize into the multiprotein complexes Polycomb Repressor Complex 1 (PRC1) and 2 (PRC2). PRC1 and PRC2 operate onto the chromatin according to a complex mechanism, which was recently recapitulated into a working model. Here, we present a functional colocalization study at 100–140 nm spatial resolution targeting PRC1 and PRC2 as well as the histone mark H3K27me3 by Image Scanning Microscopy (ISM). ISM offers a more flexible alternative to diffraction-unlimited SRMs such as STORM and STED, and it is perfectly suited to investigate the mesoscale of PRC assembly. Our data suggest a partially simultaneous effort of PRC1 and PRC2 in locally shaping the chromatin topology.

Epigenetic basis of infectious diseases

Infection refers to the invasion of the body by pathogenic microorganisms including viruses, bacteria, fungi, protozoa, and worms. Infectious diseases are the major cause of morbidity and mortality globally and represent a major threat to humankind. Infection is known to be able to profoundly alter the epigenetic state of the infected tissue. Cellular epigenome like DNA methylation and histone modification patterns is responsive to the pathogens. Host epigenetic perturbation has been evident in response to coronavirus disease-19 (COVID-19). Coronaviruses, such as MERS-CoV and SARS-CoV-1, cause host tissue epigenetic alterations by antagonizing host antigen presentation or activating interferon-response genes. The vulnerability of the elderly to SARS-CoV-2 has been linked to the effect of the epigenome on viral entry. Although numerous studies have addressed the impact of infection-induced host tissue epigenetic changes in cancer development, the broader significance of such changes remains unclear. This chapter presents novel insights on how persistent microbial infections hijack host nuclear functions and take advantage of the cellular epigenetic network to ensure microbial replication, persistence, and evasion from the host immune response. © 2023 Elsevier Inc. All rights reserved.

Introduction—Epigenetics regulations in organ specific disorders

Epigenetics is used to explain stable heritable chemical modifications to DNA and histones that affect gene expression without changing nucleotide sequence. The genetic expression of a trait in an organism can be moderated by epigenetics depending on the prevailing environmental conditions and activate different traits from the same genotype via modulating gene expression patterns. Several diseases can control or get influenced by the epigenome. A recent surge in research is focused on decoding such changes as early indicators of diseases. SARS-CoV-2, responsible for the worldwide pandemic, is also suggested to rattle the epigenetic network, impacting the host immune system negatively. While epigenetic drugs have majorly been studied in treating cancer, the increasing funding and interest have paved the way for the researchers to focus on other inflammatory diseases. The primary focus of this book has been to delineate the role of epigenetics in regulating disorders affecting organs in our body. © 2023 Elsevier Inc. All rights reserved.

COVID 19 severity is associated with the presence of lung derived cfDNA in plasma

Introduction: The presence of cfDNA in the blood is a sign of tissue damage. DNA from lung cells is rarely found in the blood of healthy subjects. We aimed to evaluate lung tissue damage among COVID19 patients and try to find out if the level of cfDNA derived from the lungs might be a predictor of disease severity. Method(s): We recruited hospitalized COVID19 patients and compared them to a control group. The control group included volunteers without current or past diagnosis of Covid19 and no history of pulmonary diseases. Blood samples for cfDNA were taken from all participants. Basic demographic and clinical information were evaluated. Six known methylation patterns typical of pulmonary origin were selected and their levels were measured in each blood sample. Statistical analysis was done to evaluate differences between the levels of cfDNA between COVID19 patients and the control group. Evaluation was done to find correlation between disease severity and cfDNA levels. Result(s): One hundred and eighteen COVID19 patients and 40 volunteers were recruited for the study. Our findings showed a significant difference of cfDNA derived from the lungs between COVID19 patients and the control group (P<0.05). The levels of cfDNA from pulmonary origin were significantly higher among patients with severe disease and were correlated with clinical variables such as mortality, need for respiratory support, chest X Ray severity and hospitalization in intensive care (P<0.05). Conclusion(s): The study demonstrated elevated levels of cfDNA among COVID19 patients. Higher levels were significantly associated with disease severity and mortality.

Effect of cigarette smoke on mucosal vaccine response with activation of plasmacytoid dendritic cells: The outcomes of in vivo and in vitro experiments.

Mucosal vaccines offer several advantages over transdermal vaccines, including the ability to acquire systemic and mucosal immunities. Smoking is a huge public health threat and major risk factor for various diseases that exacerbate or prolong respiratory symptoms and conditions. However, its impact on the efficacy of mucosal vaccines remains partially explored. Thus, this study investigates the effects of smoking on mucosal vaccine reactivity by assessing the induction of Th1 immunity, a vital response in infection defense. Cigarette smoke condensate was prepared as a substitute for mainstream smoke. We intranasally administered diphtheria toxoid as an antigen and natural CpG oligonucleotide G9.1, which enhances the Th1-type antibody (Ab) response in a plasmacytoid dendritic cells (pDCs) dependent manner, as an adjuvant to mice to assess the effect of cigarette smoke condensate on Ab responses. The mechanism of its effect was evaluated using human peripheral blood mononuclear cells and their pDC-rich fraction cultured with or without G9.1. In mice, cigarette smoke condensate tended to decrease diphtheria toxoid-specific Ab response, with a higher reduction in Th1-type IgG2 Ab response than in Th2-type IgG1 Ab response. In human peripheral blood mononuclear cells, cigarette smoke condensate significantly reduced the induction of IFN-α production by G9.1. Moreover, G9.1-induced increases in the CD83 expression in pDCs and the CD80 expression in DCs were suppressed via treatment with cigarette smoke condensate. Among the mechanisms suggested were decreased expression of toll-like receptor 9 mRNA, decreased expression of mRNA for IFN regulatory factor 7, and increased CpG methylation of its promoter region. The analysis of Tbet and GATA3 expressions revealed that cigarette smoke condensate exhibits Th1-directed immunostimulatory activity at a steady state but becomes more Th2-directed under G9.1 stimulation. In conclusion, smoking could reduce mucosal vaccine responses by decreasing pDC activation and, consequently, Th1-dominant immunity.

Identification of DNA methylation change in TCF7L2 gene in the blood of type 2 diabetes mellitus as a predictive biomarker in Iraq Kurdistan region by using methylation-specific PCR.

Objective. Nowadays, type 2 diabetes mellitus (T2D) is the most common chronic endocrine disorder affecting an estimated 5-10% of adults worldwide, and this disease also rapidly increased among the population in the Kurdistan region. This research aims to identify DNA methylation change in the TCF7L2 gene as a possible predictive T2D biomarker. Methods. One hundred and thirteen participants were divided into three groups: diabetic (47), prediabetic (36), and control (30). The study was carried out in patients who visited the private clinical sector between August and December 2021 in Koya city (Iraq Kurdistan region) to determine DNA methylation status using a methylation-specific PCR (MSP) with paired primers for each methylated and non-methylated region. In addition, the X2 Kruskal-Wallis statistical and Wilcoxon signed-rank tests were used, p<0.05 was considered significant. Results. The results showed hypermethylation of DNA in the promoter region in diabetic and prediabetic groups compared to the healthy controls. Different factors affected the DNA methylation level, including body max index, alcohol consumption, family history, and physical activity with the positive Coronavirus. Conclusion. The results obtained indicate that DNA methylation changes in the TCF7L2 promoter region may be used as a potential predictive biomarker of the T2D diagnosis. However, the findings obtained in this study should be supported by additional data.

A methylation clock model of mild SARS-CoV-2 infection provides insight into immune dysregulation.

DNA methylation comprises a cumulative record of lifetime exposures superimposed on genetically determined markers. Little is known about methylation dynamics in humans following an acute perturbation, such as infection. We characterized the temporal trajectory of blood epigenetic remodeling in 133 participants in a prospective study of young adults before, during, and after asymptomatic and mildly symptomatic SARS-CoV-2 infection. The differential methylation caused by asymptomatic or mildly symptomatic infections was indistinguishable. While differential gene expression largely returned to baseline levels after the virus became undetectable, some differentially methylated sites persisted for months of follow-up, with a pattern resembling autoimmune or inflammatory disease. We leveraged these responses to construct methylation-based machine learning models that distinguished samples from pre-, during-, and postinfection time periods, and quantitatively predicted the time since infection. The clinical trajectory in the young adults and in a diverse cohort with more severe outcomes was predicted by the similarity of methylation before or early after SARS-CoV-2 infection to the model-defined postinfection state. Unlike the phenomenon of trained immunity, the postacute SARS-CoV-2 epigenetic landscape we identify is antiprotective.