Altered DNA methylation in kidney disease: useful markers and therapeutic targets

Recent studies have demonstrated the association of altered epigenomes with lifestyle-related diseases. Epigenetic regulation promotes biological plasticity in response to environmental changes, and such plasticity may cause a ‘memory effect’, a sustained effect of transient treatment or an insult in the course of lifestyle-related diseases. We investigated the significance of epigenetic changes in several genes required for renal integrity, including the nephrin gene in podocytes, and the sustained anti-proteinuric effect, focusing on the transcription factor Krüppel-like factor 4 (KLF4). We further reported the role of the DNA repair factor lysine-acetyl transferase 5 (KAT5), which acts coordinately with KLF4, in podocyte injury caused by a hyperglycemic state through the acceleration of DNA damage and epigenetic alteration. In contrast, KAT5 in proximal tubular cells prevents acute kidney injury via glomerular filtration regulation by an epigenetic mechanism as well as promotion of DNA repair, indicating the cell type-specific action and roles of DNA repair factors. This review summarizes epigenetic alterations in kidney diseases, especially DNA methylation, and their utility as markers and potential therapeutic targets. Focusing on transcription factors or DNA damage repair factors associated with epigenetic changes may be meaningful due to their cell-specific expression or action. We believe that a better understanding of epigenetic alterations in the kidney will lead to the development of a novel strategy for chronic kidney disease (CKD) treatment.

Multi-Omics Analysis Reveals Changes in the Intestinal Microbiome, Transcriptome, and Methylome in a Rat Model of Chronic Non-bacterial Prostatitis: Indications for the Existence of the Gut-Prostate Axis

Chronic non-bacterial prostatitis (CNP) is one of the most prevalent diseases in human males worldwide. In 2005, the prostate-gut axis was first proposed to indicate the close relationship between the prostate and the intestine. This study investigated CNP-induced changes of the gut microbiota, gene expression and DNA methylation in a rat model by using multi-omics analysis. Firstly, 16S rDNA sequencing presented an altered structure of the microbiota in cecum of CNP rats. Then, transcriptomic analysis revealed that the expression of 185 genes in intestinal epithelium was significantly changed by CNP. These changes can participate in the immune system, digestive system, metabolic process, etc. Finally, methylC-capture sequencing (MCC-Seq) found 73,232 differentially methylated sites (DMSs) in the DNA of intestinal epithelium between control and CNP rats. A combined analysis of methylomics and transcriptomics suggested an epigenetic mechanism for CNP-induced differential expression genes correlated with intestinal barrier function, immunity, metabolism, enteric infectious disease, etc. More importantly, the transcriptomic, methylomic and gut microbial changes were highly correlated with multiple processes including intestinal immunity, metabolism and epithelial barrier function. In this study, disrupted homeostasis in the gut microbiota, gene expression and DNA methylation were reported in CNP, which supports the existence of the gut-prostate axis.

Profile Screening of Differentially Expressed lncRNAs of Circulating Leukocytes in Type 2 Diabetes Patients and Differences From Type 1 Diabetes

Long noncoding RNAs (lncRNAs) have been reported to have multiple functions and can be used as markers of various diseases, including diabetes. This study was conducted to determine the lncRNA profile in leukocytes from patients with type 2 diabetes (T2D). Differential expression of lncRNAs in T2D and type 1 diabetes (T1D) was also examined. RNA sequencing was performed in a critically grouped sample of leukocytes from T2D patients and healthy persons. A total of 845 significantly differentially expressed lncRNAs were identified, with 260 downregulated and 585 upregulated lncRNAs in T2D. The analysis of functions of DE-lncRNA and constructed co-expression networks (CNC) showed that 21 lncRNAs and 117 mRNAs harbored more than 10 related genes in CNC. Fourteen of 21 lncRNAs were confirmed to be significantly differentially expressed was detected by qPCR between the T2D and control validation cohorts. We also identified a panel of 4 lncRNAs showing significant differences in expression between T1D and T2D. Collectively, hundreds of novel DE-lncRNAs we identified in leukocytes from T2D patients will aid in epigenetic mechanism studies. Fourteen confirmed DE-lncRNAs can be regarded as diagnostic markers or regulators of T2D, including 4 lncRNAs that chould distinguish T1D and T2D in clinical practice to avoid misdiagnosis.

Epigenetic Modulators as Treatment Alternative to Diverse Types of Cancer

DNA is packaged in rolls in an octamer of histones forming a complex of DNA and proteins called chromatin. Chromatin as a structural matrix of a chromosome and its modifications are nowadays considered relevant aspects for regulating gene expression, which has become of high interest in understanding genetic mechanisms regulating various diseases, including cancer. In various types of cancer, the main modifications are found to be DNA methylation in the CpG dinucleotide as a silencing mechanism in transcription, post-translational histone modifications such as acetylation, methylation and others that affect the chromatin structure, the ATP-dependent chromatin remodeling and miRNA-mediated gene silencing. In this review we analyze the main alterations in gene expression, the epigenetic modification patterns that cancer cells present, as well as the main modulators and inhibitors of each epigenetic mechanism and the molecular evolution of the most representative inhibitors, which have opened a promising future in the study of HAT, HDAC, non-glycoside DNMT inhibitors and domain inhibitors.

A Comprehensive In Silico Perspective For Discovery of Novel Inhibitory Candidates Targeting Versatile Transcriptional Repressor MBD2

Genome methylation is a key epigenetic mechanism in various biological events such as development, cellular differentiation, cancer progression, aging, and iPSC reprogramming. Crosstalk between DNA methylation and regulation in gene expression is employed through MBD2, known as reader of DNA methylation and suggested as a drug target. Despite its magnitude of significance and rationale of nomination, a scarcely limited number of druggable ligands has been detected so far. Hence, we screened a comprehensive compound library, and then certain of them were subjected to computational docking analysis by targeting the methylated DNA-binding domain of human MBD2. We could detect reasonable binding energies and docking residues presumably located in druggable pockets. Docking results were also validated via MD simulation and per-residue energy decomposition calculation. Drug-likeness of tested ligands was assessed through ADMET prediction in order to foresee off-target side effects for future studies. Herein, on the basis of collaborating approaches such as molecular docking, MD simulation, energy decomposition, and ADMET prediction, notably two compounds named CID3100583 and 8,8-Ethylenebistheophylline, have become prominent as novel candidates, possibly disrupting MBD2MBD–DNA interaction. Hereby, these compounds exhibit a promising usage potential in a wide range of implementations from cancer treatment to somatic cell reprogramming protocols.

Usefulness of Melatonin and Other Compounds as Antioxidants and Epidrugs in the Treatment of Head and Neck Cancer

Along with genetic mutations, aberrant epigenetic alterations are the initiators of head and neck cancer carcinogenesis. Currently, several drugs are being developed to correct these epigenetic alterations, known as epidrugs. Some compounds with an antioxidant effect have been shown to be effective in preventing these malignant lesions and in minimizing the complications derived from cytotoxic treatment. Furthermore, in vitro and in vivo studies show a promising role in the treatment of head and neck squamous cell carcinoma (HNSCC). This is the case of supplements with DNA methylation inhibitory function (DNMTi), such as epigallocatechin gallate, sulforaphane, and folic acid; histone deacetylase inhibitors (HDACi), such as sodium butyrate and melatonin or histone acetyltransferase inhibitors (HATi), such as curcumin. The objective of this review is to describe the role of some antioxidants and their epigenetic mechanism of action, with special emphasis on melatonin and butyric acid given their organic production, in the prevention and treatment of HNSCC.

Programming of obesity and pediatric metabolic syndromes: a review in light of epigenetic modulation

Obesity is a multifactorial health problem characterized by the excessive accumulation of fat in the body and affects approximately 338 million children and adolescents worldwide. For this reason, this study consisted of a literature review to investigate how the causes and treatments of pediatric obesity are being addressed in light of epigenetic modulation as a factor in metabolic programming. For this, preferentially original articles published in English between the years 2017 to 2021 in the PubMed and Scholar Google databases were searched using the epigenetics descriptors; epigenetic modulation; child obesity; metabolic syndrome, combined with each other. A total of 54,000 articles were returned to searches in PubMed and 16,107,000 in Scholar Google. Fewer than 500 studies jointly addressed epigenetics and aspects of obesity or metabolic syndromes in childhood. Only 14 works matched the search criteria. The most discussed epigenetic mechanism in the literature is DNA methylation, whose rates observed mainly in CpG islands of promoter regions in several genes contribute to the prevention and early diagnosis of obesity and other pediatric comorbidities even before birth, based on the correlation between the epigenetic marks, maternal and paternal health and anthropometric indices. Although experimental studies on infant metabolic programming are scarce, existing knowledge suggests that environmental, nutritional, and energy expenditure changes are capable of modulating the epigenome and reversing marks that induce susceptibility to metabolic comorbidities.

Electromagnetic Information Transfer (EMIT) by Ultra High Diluted (UHD) solutions: the suggestive hypothesis of an epigenetic action.

The aim of this work is to confirm the theoretical possibility of an epigenetic mechanism shared between EMIT and UHD. The presentation will be divided in three sections: 1. Water aggregates with an electric dipole moment (UHD succussed solutions) as mediators of weak specific bioelectromagnetic signals on target stem cells. Recent experimental works confirm the developing concept of water mediated Electromagnetic Information Transfer (EMIT) of specific molecular signals, picked up from the source biological effector, on target stem cells with evident effect on their proliferation [1]. Similar Electromagnetic (EM) emission and consequences are also reported by the scientific literature on rotational excited aggregates with an electric dipole moment, created in polar liquids by Ultra High Diluted (UHD) or High Diluted (HD) succussed solutions. These aggregates are composed of solvent molecules only or a combination of these and solute particles [2]. 2. DNA mediated physiopathological effects of ELF EMFs In detail, according to the International Agency for Research on Cancer (IARC), the extremely low-frequency (ELF) electromagnetic fields (EMFs) are classified as "possible carcinogenic" based on their effects [3-5], although most scientists agree that they are too weak to kill cells or to cause mutations and thus initiate cancer. Besides the prevailing paradigm of the environmentally-induced acute and chronic diseases involving either cell killing (cytotoxicity) or gene/chromosome mutations (genotoxicity), many studies concerning the biological and health consequences of ELF-EM exposure report that alteration of the expression of genetic information at the transcriptional, translational, or posttranslational levels has the potential to contribute to various diseases. 3. Epigenetic mechanism shared between EMIT and UHDs The latter referred mechanism, denoted as "epigenetic" (that affects gene expression rather than gene structure), is characterized by threshold-like action, multiple biochemical pathways and it needs chronic regular exposures to be effective [6]. Epigenetic factors affect one of four potential cell states, namely alteration of cell proliferation, cell differentiation, programmed cell death (apoptosis) or adaptive responses of differentiated cells, and probably they act as co-inductors of DNA damage rather than as a genotoxic agents per se. At the present time, studies on genomic and functional genetic are identifying many genes and gene variants that potentially modulate the fundamental molecular mechanisms underpinning both physiological and pathological processes.

The impact of Piscirickettsia Salmonis infection on genome-wide DNA methylation profile in Atlantic Salmon

Salmon rickettsial septicaemia (SRS), caused by the intracellular bacteria Piscirickettsia Salmonis, generates significant mortalities to farmed Atlantic salmon, particularly in Chile. Due to its economic importance, a wealth of research has focussed on the biological mechanisms underlying pathogenicity of P. salmonis, the host response, and genetic variation in host resistance. DNA methylation is a fundamental epigenetic mechanism that influences almost every biological process via the regulation of gene expression and plays a key role in the response of an organism to stimuli. In the current study, the role of head kidney and liver DNA methylation in the response to P. salmonis infection was investigated in a commercial Atlantic salmon population. A total of 66 salmon were profiled using reduced representation bisulphite sequencing (RRBS), with head kidney and liver methylomes compared between infected animals (3 and 9 days post infection) and uninfected controls. These included groups of salmon with divergent (high or low) breeding values for resistance to P. salmonis infection, to examine the influence of genetic resistance. Head kidney and liver showed organ-specific global methylation patterns, but with similar distribution of methylation across gene features. Integration of methylation with RNA-Seq data revealed that methylation levels predominantly showed a negative correlation with gene expression, although positive correlations were also observed. Methylation within the first exon showed the strongest negative correlation with gene expression. A total of 911 and 813 differentially methylated CpG sites were identified between infected and control samples in the head kidney at 3 and 9 days respectively, whereas only 30 and 44 sites were differentially methylated in the liver. Differential methylation in the head kidney was associated with immunological processes such as actin cytoskeleton regulation, phagocytosis, endocytosis and pathogen associated pattern receptor signaling. We also identified 113 and 48 differentially methylated sites between resistant and susceptible fish in the head kidney and liver respectively. Our results contribute to the growing understanding of the role of methylation in regulation of gene expression and response to infectious diseases, and in particular reveal key immunological functions regulated by methylation in Atlantic salmon in response to P. salmonis.

Prenatal Iron Deficiency and Choline Supplementation Interact to Epigenetically Regulate Jarid1b and Bdnf in the Rat Hippocampus into Adulthood

Early-life iron deficiency (ID) causes long-term neurocognitive impairments and gene dysregulation that can be partially mitigated by prenatal choline supplementation. The long-term gene dysregulation is hypothesized to underlie cognitive dysfunction. However, mechanisms by which iron and choline mediate long-term gene dysregulation remain unknown. In the present study, using a well-established rat model of fetal-neonatal ID, we demonstrated that ID downregulated hippocampal expression of the gene encoding JmjC-ARID domain-containing protein 1B (JARID1B), an iron-dependent histone H3K4 demethylase, associated with a higher histone deacetylase 1 (HDAC1) enrichment and a lower enrichment of acetylated histone H3K9 (H3K9ac) and phosphorylated cAMP response element-binding protein (pCREB). Likewise, ID reduced transcriptional capacity of the gene encoding brain-derived neurotrophic factor (BDNF), a target of JARID1B, associated with repressive histone modifications such as lower H3K9ac and pCREB enrichments at the Bdnf promoters in the adult rat hippocampus. Prenatal choline supplementation did not prevent the ID-induced chromatin modifications at these loci but induced long-lasting repressive chromatin modifications in the iron-sufficient adult rats. Collectively, these findings demonstrated that the iron-dependent epigenetic mechanism mediated by JARID1B accounted for long-term Bdnf dysregulation by early-life ID. Choline supplementation utilized a separate mechanism to rescue the effect of ID on neural gene regulation. The negative epigenetic effects of choline supplementation in the iron-sufficient rat hippocampus necessitate additional investigations prior to its use as an adjunctive therapeutic agent.