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Direction-aware functional class scoring enrichment analysis of infinium DNA methylation data.

Infinium Methylation BeadChip arrays remain one of the most popular platforms for epigenome-wide association studies, but tools for downstream pathway analysis have their limitations. Functional class scoring (FCS) is a group of pathway enrichment techniques that involve the ranking of genes and evaluation of their collective regulation in biological systems, but the implementations described for Infinium methylation array data do not retain direction information, which is important for mechanistic understanding of genomic regulation. Here, we evaluate several candidate FCS methods that retain

The effect of N6-methyladenosine (m6A) factors on the development of acute respiratory distress syndrome in the mouse model.

Acute respiratory distress syndrome (ARDS) can cause loss of alveolar-capillary membrane integrity and life-threatening immune responses. The underlying molecular mechanisms of ARDS remain unclear. N6-methyladenosine (m6A)-RNA modification plays an important part in many biological processes. However, it is not clear whether ARDS alters RNA methylation in lung tissue. We tried to investigate the changes of m6A-RNA methylation in lung tissues of lipopolysaccharide (LPS)-induced ARDS mice. Lung tissue samples were collected to detect the expression of m6A factors through hematoxylin and eosin (H…

Genome-wide profiling of m6A modification and its role in the transcriptome of sequelae of pelvic inflammatory disease.

Sequelae of pelvic inflammatory disease (SPID), such as chronic pelvic pain and infertility, are major long-term complications that signific … ptional profile in the peripheral blood of SPID patients, revealed potential relationships between mRNA methylation and SPID-related genes, and suggested that m6A modification may be related to the occurrence and progression of SPID.

Developmental and Injury-induced Changes in DNA Methylation in Regenerative versus Non-regenerative Regions of the Vertebrate Central Nervous System.

BACKGROUND: Because some of its CNS neurons (e.g., retinal ganglion cells after optic nerve crush (ONC)) regenerate axons throughout life, whereas others (e.g., hindbrain neurons after spinal cord injury (SCI)) lose this capacity as tadpoles metamorphose into frogs, the South African claw-toed frog, Xenopus laevis, offers unique opportunities for exploring differences between regenerative and non-regenerative responses to CNS injury within the same organism. An earlier, three-way RNA-seq study (frog ONC eye, tadpole SCI hindbrain, frog SCI hindbrain) identified genes that regulate chromatin ac

The Genome-wide Methylation Profile of CD4+ T Cells From Individuals With Human Immunodeficiency Virus (HIV) Identifies Distinct Patterns Associated With Disease Progression.

BACKGROUND: Human genetic variation-mostly in the human leukocyte antigen (HLA) and C-C chemokine receptor type 5 (CCR5) regions-explains 25% of the variability in progression of human immunodeficiency virus (HIV) infection. However, it is also known that viral infections can modify cellular DNA methylation patterns. Therefore, changes in the methylation of cytosine-guanine (CpG) islands might modulate progression of HIV infection. METHODS: In total, 85 samples were analyzed: 21 elite controllers (EC), 21 subjects with HIV before combination antiretroviral therapy (cART) (viremic, 93 325 huma

Inhibition of Japanese encephalitis virus (JEV) replication by specific RNA aptamer against JEV methyltransferase.

Japanese encephalitis virus (JEV) is the most common etiological agent of epidemic viral encephalitis. JEV encodes a single methyltransferase (MTase) domain located at the N-terminal region of the viral nonstructural protein NS5. JEV MTase is essential for viral replication and specifically catalyzes methylation of the viral RNA cap, which occurs exclusively in the cytoplasm. Therefore, JEV MTase is a potential target for antiviral therapy. Here, we identified specific and avid RNA aptamer (Kd ∼ 12 nM) with modified 2'-O-methyl pyrimidines against JEV MTase. The RNA aptamer efficiently inhibit

Inhibition of Mettl3-mediated m6A RNA modification of HMGCS1 protects retinal ganglion cells from glutamate excitotoxicity-induced ferroptosis in a rat model of glaucoma.

BACKGROUND: Glaucoma, a leading cause of irreversible blindness worldwide, is characterized by progressive retinal ganglion cells (RGCs) degeneration. The accumulation of glutamate in the retina is a common mechanism underlying the of RGCs death in various forms of glaucoma. Neuroprotective strategies for RGCs remain an unmet need, urging exploration of novel molecular mechanisms beyond intraocular pressure (IOP) control. MATERIALS AND METHODS: Retinal m6A methylation sequencing, RT-qPCR, and dot blot techniques were performed to identify m6A methylation levels change in an N-methyl-D-asparta

A tale of two parasites: a glimpse into the RNA methylome of patient-derived Plasmodium falciparum and Plasmodium vivax isolates.

BACKGROUND: Understanding the molecular mechanisms of the malarial parasites in hosts is crucial for developing effective treatments. Epitranscriptomic research on pathogens has unveiled the significance of RNA methylation in gene regulation and pathogenesis. This is the first report investigating methylation signatures and alternative splicing events using Nanopore Direct RNA Sequencing to single-base resolution in Plasmodium falciparum and Plasmodium vivax clinical isolates with hepatic dysfunction complications. METHODS: Direct RNA Sequencing using Nanopore from clinical isolates of P. fal…

Targeting epigenetic methylation: emerging diagnosis and therapeutic strategies in cancer.

Epigenetics shapes all aspects of cancer occurrence and progression. Among them, chromatin methylation is a particularly important regulator of oncogenic processes. The dynamic shifts in methylation can influence the development or death of tumor cells. In the therapeutic context, effectively targeting and modulating DNA, RNA, and histone methylation brings promise for the early detection, prognostic assessment, and treatment of cancer. In particular, novel methylation inhibitors or modulators powerfully kill tumor cells or improve existing therapeutic strategies through different signaling pa

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… Subsequent decades of research identified major forms of RNA methylation [ 7 ] and histone methyltransferases [ 8 ]. … Inhibitors of RNA methylation To date, there has only been relatively limited success in the development and clinical application of RNA methylation inhibitors. FTO and METTL3 inhibitors are the only small molecules that have been widely utilized in research settings. …

HNRNPC mediated m6A methylation of 5-methyltetrahydrofolate-homocysteine methyltransferase and involved in the occurrence of RSA.

N6-methyladenosine methylated modification has been shown to play roles in recurrent spontaneous abortion. We aimed to explore role of heterogeneous nuclear ribonucleoprotein C in the occurrence of recurrent spontaneous abortion. We collected embryonic villous tissues from 3 patients with recurrent spontaneous abortion (RSA group) and 3 normal control pregnancy patients. Methylated RNA immunoprecipitation sequencing, RNA sequencing, methylated RNA immunoprecipitation quantitative PCR were conducted to detect the differentially expressed m6A methylation modification gene and regulatory gene in

Insights into the epitranscriptomic role of N6-methyladenosine on aging skeletal muscle.

The modification of RNA through the N6-methyladenosine (m6A) has emerged as a growing area of research due to its regulatory role in gene expression and various biological processes regulating the expression of genes. m6A RNA methylation is a post-transcriptional modification that is dynamic and reversible and found in mRNA, tRNA, rRNA, and other non-coding RNA of most eukaryotic cells. It is executed by special proteins known as "writers," which initiate methylation; "erasers," which remove methylation; and "readers," which recognize it and regulate the expression of the gene. Modification by…

Epitranscriptomic analysis reveals clinical and molecular signatures in glioblastoma.

This study characterizes the glioblastoma (GB) epitranscriptomic landscape in patient who evolve to progressive disease (PD) or pseudo-progressive disease (psPD). Novel differences in N6-Methyladenosine (m6A) RNA methylation patterns between these groups are identified in the first biopsy. Retrospective data of patients that were eventually deemed to have progressive disease or pseudoprogressive disease was captured from the electronic health record, and RNA from the first resection specimen was utilized to evaluate N6-methyladenosine (m6A) biomarkers from FFPE samples. Molecular analysis of m…

N6-Methyladenosine methylase METTL3 contributes to neuropathic pain by epigenetic silencing of mu opioid receptor.

We aimed at exploring the role and mechanism of METTL3-mediated m6A modification in neuropathic pain. Male Sprague-Dawley rats were randomly divided into four groups: Sham operation group (Sham group), chronic constriction injury (CCI) of the sciatic nerve model group (NPP group), intrathecal injection of virus down-regulated METTL3 + CCI model group (M3 + NPP group) and intrathecal injection of negative control virus + CCI model group (Scr + NPP group). The M3 + NPP group and the Scr + NPP group were intrathecally injected with virus nineteen days before operation. The paw withdrawal mechanic

Methylations in dilated cardiomyopathy and heart failure.

Dilated cardiomyopathy (DCM) is characterized by impaired expansion or contraction of the left or both ventricles in the absence of abnormal … athogenesis of hypertension, cardiac hypertrophy, and atherosclerosis is well-established. Of late, RNA methylation has garnered attention for its involvement in DCM. This review examines the biological mechanisms and effects of RNA methylation in DCM and heart failure.

The zinc-finger protein SPT4 interacts with SPT5L/KTF1 and modulates transcriptional silencing in Arabidopsis.

The Arabidopsis multidomain protein SPT5L/KTF1 (which has similarity to the transcript elongation factor SPT5) associates with RNA polymerase V (RNAPV) and is an accessory factor in RNA-directed DNA methylation. The zinc-finger protein SPT4 was found to interact with SPT5L (and SPT5) both in vivo and in vitro. Here, we show that plants depleted of SPT4 relative to wild type display reduced DNA methylation and the locus specificity is shared with SPT5L, suggesting a cooperation of SPT4 and SPT5L. Unlike observed for SPT5, no reduced protein level of SPT5L is determined in SPT4-deficient plants.

NSUN2-mediated GATM m5C methylation regulates creatine metabolism to drive mitochondrial fission and promote renal fibrosis.

Chronic kidney disease (CKD) is increasing globally, presenting a critical health challenge. Renal fibrosis, the main pathological feature of CKD, is poorly understood and lacks targeted therapies. Here, we reveal that 5-methylcytosine (m5C) RNA methylation, primarily mediated by methyltransferase NSUN2, is significantly upregulated in renal fibrosis. Reduction of m5C RNA methylation levels upon NSUN2 loss attenuates fibrosis responses in cells, and specific knockout of NSUN2 in renal tubular epithelial cells alleviates renal fibrosis in several disease models. Mechanistically, NSUN2 methylate…

Site-specific inhibition of translation initiation via 2'-O-methylation.

Translation initiation involves a concerted set of intermolecular interactions that efficiently recognize optimal AUG start codons. However, translation initiation complexes often start at upstream non-optimal AUGs or near-cognate codons, leading to the expression of upstream open reading frames (uORFs). Using retrospective analyses of translation preinitiation cryo-EM structures, we identified putative hydrogen bonds between the 2'-OH groups of messenger RNA (mRNA) start codons with 18S ribosomal RNA. Disruption of these interactions using a chemical modification of mRNA, 2'-O-methylation (Nm

Shaping Spliceosome Dynamics Through Protein Arginine Methylation.

Accurate removal of intervening intronic sequences from pre-mRNA is required for proper eukaryotic gene expression. This process, termed pre-mRNA splicing, is carried out by a spliceosome, a dynamic RNA-protein macromolecular machinery. Proteomic studies have shown that many spliceosomal components and associated factors harbor protein arginine methylation, a type of post-translational modification. These findings raise the question of how arginine methylation influences the process or outcome of pre-mRNA splicing. Although targeted studies have provided important molecular insights into how t

Determination of RNA Hydroxylmethylation in Mammals by Mass Spectrometry Analysis.

RNA molecules harbor diverse chemical modifications that play important regulatory roles in a variety of biological processes. Up to date, more than 150 modifications have been identified in various RNA species. Most of these modifications occurring in nucleic acids are the methylation of nucleic acids. It has been demonstrated that many of these methylation are reversible and undergo dynamic demethylation. Previous studies established that the demethylation of the two most important and prevalent modifications of 5-methylcytidine (m5C) and N6-methyladenosine (m6A) in nucleic acids is through

Unique methylation pattern of oncostatin m receptor gene in cancers of colorectum and other digestive organs.

PURPOSE: Oncostatin M (OSM) is an interleukin-6 cytokine family member, which inhibits cell proliferation and induces cell differentiation and apoptosis in cancers. In melanoma cells, epigenetic silencing of OSM receptor (OSMR) by histone deacetylation contributes to escape of cell growth control by OSM. However, the silencing of OSMR by DNA methylation in any cancer has not been examined. EXPERIMENTAL DESIGN: Methylation status of OSMR was determined by sequencing or methylation-specific PCR in primary tumors and cell lines. Cell lines were treated with DNA methyltransferase inhibitors 5-aza