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Nucleic Acids Research Aug 2023Integrative analysis of multi-omic datasets has proven to be extremely valuable in cancer research and precision medicine. However, obtaining multimodal data from the...
Integrative analysis of multi-omic datasets has proven to be extremely valuable in cancer research and precision medicine. However, obtaining multimodal data from the same samples is often difficult. Integrating multiple datasets of different omics remains a challenge, with only a few available algorithms developed to solve it. Here, we present INTEND (IntegratioN of Transcriptomic and EpigeNomic Data), a novel algorithm for integrating gene expression and DNA methylation datasets covering disjoint sets of samples. To enable integration, INTEND learns a predictive model between the two omics by training on multi-omic data measured on the same set of samples. In comprehensive testing on 11 TCGA (The Cancer Genome Atlas) cancer datasets spanning 4329 patients, INTEND achieves significantly superior results compared with four state-of-the-art integration algorithms. We also demonstrate INTEND's ability to uncover connections between DNA methylation and the regulation of gene expression in the joint analysis of two lung adenocarcinoma single-omic datasets from different sources. INTEND's data-driven approach makes it a valuable multi-omic data integration tool. The code for INTEND is available at https://github.com/Shamir-Lab/INTEND.
Topics: Humans; DNA Methylation; Neoplasms; Algorithms; Gene Expression Profiling; Transcriptome
PubMed: 37395437
DOI: 10.1093/nar/gkad566 -
Plant Cell Reports Aug 2020RNA Directed DNA Methylation (RdDM) is a pathway that mediates de novo DNA methylation, an evolutionary conserved chemical modification of cytosine bases, which exists... (Review)
Review
RNA Directed DNA Methylation (RdDM) is a pathway that mediates de novo DNA methylation, an evolutionary conserved chemical modification of cytosine bases, which exists in living organisms and utilizes small interfering RNA. Plants utilize DNA methylation for transposable element (TE) repression, regulation of gene expression and developmental regulation. TE activity strongly influences genome size and evolution, therefore making DNA methylation a key component in understanding divergence in genome evolution among seed plants. Multiple proteins that have extensively been studied in model plant Arabidopsis thaliana catalyze RNA dependent DNA Methylation pathway along with small interfering RNA. Several developmental functions have also been attributed to DNA methylation. This review will highlight aspects of RdDM pathway dynamics, evolution and functions in seed plants with focus on recent findings on conserved and non-conserved attributes between angiosperms and gymnosperms to potentially explain how methylation has impacted variations in evolutionary and developmental complexity among them and advance current understanding of this crucial epigenetic pathway.
Topics: DNA Methylation; Evolution, Molecular; Gene Expression Regulation, Plant; Genome, Plant; RNA, Plant; Seeds
PubMed: 32594202
DOI: 10.1007/s00299-020-02558-4 -
Dialogues in Clinical Neuroscience Sep 2014Dynamic regulation of chromatin structure in postmitotic neurons plays an important role in learning and memory. Methylation of cytosine nucleotides has historically... (Review)
Review
Dynamic regulation of chromatin structure in postmitotic neurons plays an important role in learning and memory. Methylation of cytosine nucleotides has historically been considered the strongest and least modifiable of epigenetic marks. Accumulating recent data suggest that rapid and dynamic methylation and demethylation of specific genes in the brain may play a fundamental role in learning, memory formation, and behavioral plasticity. The current review focuses on the emergence of data that support the role of DNA methylation and demethylation, and its molecular mediators in memory formation.
Topics: Animals; DNA Methylation; Epigenomics; Humans; Learning; Memory; Methyltransferases
PubMed: 25364286
DOI: 10.31887/DCNS.2014.16.3/mmorris -
BMB Reports Nov 2017Aging is a natural and gradual process in human life. It is influenced by heredity, environment, lifestyle, and disease. DNA methylation varies with age, and the ability... (Review)
Review
Aging is a natural and gradual process in human life. It is influenced by heredity, environment, lifestyle, and disease. DNA methylation varies with age, and the ability to predict the age of donor using DNA from evidence materials at a crime scene is of considerable value in forensic investigations. Recently, many studies have reported age prediction models based on DNA methylation from various tissues and body fluids. Those models seem to be very promising because of their high prediction accuracies. In this review, the changes of age-associated DNA methylation and the age prediction models for various tissues and body fluids were examined, and then the applicability of the DNA methylation-based age prediction method to the forensic investigations was discussed. This will improve the understandings about DNA methylation markers and their potential to be used as biomarkers in the forensic field, as well as the clinical field. [BMB Reports 2017; 50(11): 546-553].
Topics: Age Factors; Biomarkers; Body Fluids; CpG Islands; DNA; DNA Methylation; Forecasting; Forensic Genetics; Humans
PubMed: 28946940
DOI: 10.5483/bmbrep.2017.50.11.175 -
Cells Aug 2019Rheumatoid arthritis (RA) is a long-term autoimmune disease of unknown etiology that leads to progressive joint destruction and ultimately to disability. RA affects as... (Review)
Review
Rheumatoid arthritis (RA) is a long-term autoimmune disease of unknown etiology that leads to progressive joint destruction and ultimately to disability. RA affects as much as 1% of the population worldwide. To date, RA is not a curable disease, and the mechanisms responsible for RA development have not yet been well understood. The development of more effective treatments and improvements in the early diagnosis of RA is direly needed to increase patients' functional capacity and their quality of life. As opposed to genetic mutation, epigenetic changes, such as DNA methylation, are reversible, making them good therapeutic candidates, modulating the immune response or aggressive synovial fibroblasts (FLS-fibroblast-like synoviocytes) activity when it is necessary. It has been suggested that DNA methylation might contribute to RA development, however, with insufficient and conflicting results. Besides, recent studies have shown that circulating cell-free methylated DNA (ccfDNA) in blood offers a very convenient, non-invasive, and repeatable "liquid biopsy", thus providing a reliable template for assessing molecular markers of various diseases, including RA. Thus, epigenetic therapies controlling autoimmunity and systemic inflammation may find wider implications for the diagnosis and management of RA. In this review, we highlight current challenges associated with the treatment of RA and other autoimmune diseases and discuss how targeting DNA methylation may improve diagnostic, prognostic, and therapeutic approaches.
Topics: Animals; Arthritis, Rheumatoid; DNA Methylation; Humans
PubMed: 31443448
DOI: 10.3390/cells8090953 -
Clinical Epigenetics Apr 2021Congenital heart disease (CHD) is a common structural birth defect worldwide, and defects typically occur in the walls and valves of the heart or enlarged blood vessels.... (Review)
Review
Congenital heart disease (CHD) is a common structural birth defect worldwide, and defects typically occur in the walls and valves of the heart or enlarged blood vessels. Chromosomal abnormalities and genetic mutations only account for a small portion of the pathogenic mechanisms of CHD, and the etiology of most cases remains unknown. The role of epigenetics in various diseases, including CHD, has attracted increased attention. The contributions of DNA methylation, one of the most important epigenetic modifications, to CHD have not been illuminated. Increasing evidence suggests that aberrant DNA methylation is related to CHD. Here, we briefly introduce DNA methylation and CHD and then review the DNA methylation profiles during cardiac development and in CHD, abnormalities in maternal genome-wide DNA methylation patterns are also described. Whole genome methylation profile and important differentially methylated genes identified in recent years are summarized and clustered according to the sample type and methodologies. Finally, we discuss the novel technology for and prospects of CHD-related DNA methylation.
Topics: DNA Methylation; Epigenesis, Genetic; Heart Defects, Congenital; Humans
PubMed: 33902696
DOI: 10.1186/s13148-021-01077-7 -
Cell Research Mar 2011DNA methylation is an important epigenetic mark involved in diverse biological processes. In plants, DNA methylation can be established through the RNA-directed DNA... (Review)
Review
DNA methylation is an important epigenetic mark involved in diverse biological processes. In plants, DNA methylation can be established through the RNA-directed DNA methylation pathway, an RNA interference pathway for transcriptional gene silencing (TGS), which requires 24-nt small interfering RNAs. In mammals, de novo DNA methylation occurs primarily at two developmental stages: during early embryogenesis and during gametogenesis. While it is not clear whether establishment of DNA methylation patterns in mammals involves RNA interference in general, de novo DNA methylation and suppression of transposons in germ cells require 24-32-nt piwi-interacting small RNAs. DNA methylation status is dynamically regulated by DNA methylation and demethylation reactions. In plants, active DNA demethylation relies on the repressor of silencing 1 family of bifunctional DNA glycosylases, which remove the 5-methylcytosine base and then cleave the DNA backbone at the abasic site, initiating a base excision repair (BER) pathway. In animals, multiple mechanisms of active DNA demethylation have been proposed, including a deaminase- and DNA glycosylase-initiated BER pathway. New information concerning the effects of various histone modifications on the establishment and maintenance of DNA methylation has broadened our understanding of the regulation of DNA methylation. The function of DNA methylation in plants and animals is also discussed in this review.
Topics: Animals; Arabidopsis; Arabidopsis Proteins; DNA (Cytosine-5-)-Methyltransferases; DNA Glycosylases; DNA Methylation; DNA Repair; Gene Silencing
PubMed: 21321601
DOI: 10.1038/cr.2011.23 -
Journal of Integrative Plant Biology Dec 2022DNA methylation plays essential homeostatic functions in eukaryotic genomes. In animals, DNA methylation is also developmentally regulated and, in turn, regulates... (Review)
Review
DNA methylation plays essential homeostatic functions in eukaryotic genomes. In animals, DNA methylation is also developmentally regulated and, in turn, regulates development. In the past two decades, huge research effort has endorsed the understanding that DNA methylation plays a similar role in plant development, especially during sexual reproduction. The power of whole-genome sequencing and cell isolation techniques, as well as bioinformatics tools, have enabled recent studies to reveal dynamic changes in DNA methylation during germline development. Furthermore, the combination of these technological advances with genetics, developmental biology and cell biology tools has revealed functional methylation reprogramming events that control gene and transposon activities in flowering plant germlines. In this review, we discuss the major advances in our knowledge of DNA methylation dynamics during male and female germline development in flowering plants.
Topics: Animals; DNA Methylation; Epigenesis, Genetic; Germ Cells; Reproduction
PubMed: 36478632
DOI: 10.1111/jipb.13422 -
Bone Mar 2016Although there is a documented social gradient for osteoporosis, the underlying mechanism(s) for that gradient remain unknown. We propose a conceptual model based upon... (Review)
Review
INTRODUCTION
Although there is a documented social gradient for osteoporosis, the underlying mechanism(s) for that gradient remain unknown. We propose a conceptual model based upon the allostatic load theory, to suggest how DNA methylation (DNAm) might underpin the social gradient in osteoporosis and fracture. We hypothesise that social disadvantage is associated with priming of inflammatory pathways mediated by epigenetic modification that leads to an enhanced state of inflammatory reactivity and oxidative stress, and thus places socially disadvantaged individuals at greater risk of osteoporotic fracture.
METHODS/RESULTS
Based on a review of the literature, we present a conceptual model in which social disadvantage increases stress throughout the lifespan, and engenders a proinflammatory epigenetic signature, leading to a heightened inflammatory state that increases risk for osteoporotic fracture in disadvantaged groups that are chronically stressed.
CONCLUSIONS
Our model proposes that, in addition to the direct biological effects exerted on bone by factors such as physical activity and nutrition, the recognised socially patterned risk factors for osteoporosis also act via epigenetic-mediated dysregulation of inflammation. DNAm is a dynamic modulator of gene expression with considerable relevance to the field of osteoporosis. Elucidating the extent to which this epigenetic mechanism transduces the psycho-social environment to increase the risk of osteoporotic fracture may yield novel entry points for intervention that can be used to reduce individual and population-wide risks for osteoporotic fracture. Specifically, an epigenetic evidence-base may strengthen the importance of lifestyle modification and stress reduction programs, and help to reduce health inequities across social groups.
MINI ABSTRACT
Our conceptual model proposes how DNA methylation might underpin the social gradient in osteoporotic fracture. We suggest that social disadvantage is associated with priming of inflammatory signalling pathways, which is mediated by epigenetic modifications, leading to a chronically heightened inflammatory state that places disadvantaged individuals at greater risk of osteoporosis.
Topics: Aging; DNA Methylation; Epigenesis, Genetic; Humans; Models, Biological; Osteoporotic Fractures; Socioeconomic Factors
PubMed: 26723576
DOI: 10.1016/j.bone.2015.12.015 -
Essays in Biochemistry Oct 2020Cells encounter a multitude of external and internal stress-causing agents that can ultimately lead to DNA damage, mutations and disease. A cascade of signaling events... (Review)
Review
Cells encounter a multitude of external and internal stress-causing agents that can ultimately lead to DNA damage, mutations and disease. A cascade of signaling events counters these challenges to DNA, which is termed as the DNA damage response (DDR). The DDR preserves genome integrity by engaging appropriate repair pathways, while also coordinating cell cycle and/or apoptotic responses. Although many of the protein components in the DDR are identified, how chemical modifications to DNA impact the DDR is poorly understood. This review focuses on our current understanding of DNA methylation in maintaining genome integrity in mammalian cells. DNA methylation is a reversible epigenetic mark, which has been implicated in DNA damage signaling, repair and replication. Sites of DNA methylation can trigger mutations, which are drivers of human diseases including cancer. Indeed, alterations in DNA methylation are associated with increased susceptibility to tumorigenesis but whether this occurs through effects on the DDR, transcriptional responses or both is not entirely clear. Here, we also highlight epigenetic drugs currently in use as therapeutics that target DNA methylation pathways and discuss their effects in the context of the DDR. Finally, we pose unanswered questions regarding the interplay between DNA methylation, transcription and the DDR, positing the potential coordinated efforts of these pathways in genome integrity. While the impact of DNA methylation on gene regulation is widely understood, how this modification contributes to genome instability and mutations, either directly or indirectly, and the potential therapeutic opportunities in targeting DNA methylation pathways in cancer remain active areas of investigation.
Topics: Animals; DNA Methylation; Genome; Humans
PubMed: 32808652
DOI: 10.1042/EBC20200009