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Nature Aging Dec 2021DNA methylation dynamics emerged as a promising biomarker of mammalian aging, with multivariate machine learning models ('epigenetic clocks') enabling measurement of...
DNA methylation dynamics emerged as a promising biomarker of mammalian aging, with multivariate machine learning models ('epigenetic clocks') enabling measurement of biological age in bulk tissue samples. However, intrinsically sparse and binarized methylation profiles of individual cells have so far precluded the assessment of aging in single-cell data. Here, we introduce , a statistical framework for epigenetic age profiling at single-cell resolution, and validate our approach in mice. Our method recapitulates the chronological age of tissues, while uncovering heterogeneity among cells. We show accurate tracking of the aging process in hepatocytes, demonstrate attenuated epigenetic aging in muscle stem cells, and track age dynamics in embryonic stem cells. We also use to reveal, at the single-cell level, a natural and stratified rejuvenation event occurring during early embryogenesis. We provide our framework as a resource to enable exploration of epigenetic aging trajectories at single-cell resolution.
Topics: Animals; Mice; Epigenesis, Genetic; Aging; DNA Methylation; Biomarkers; Hepatocytes; Mammals
PubMed: 36211119
DOI: 10.1038/s43587-021-00134-3 -
Biomolecules Dec 2020Liquid biopsy based on cell-free DNA (cfDNA) enables non-invasive dynamic assessment of disease status in patients with cancer, both in the early and advanced settings.... (Review)
Review
Liquid biopsy based on cell-free DNA (cfDNA) enables non-invasive dynamic assessment of disease status in patients with cancer, both in the early and advanced settings. The analysis of DNA-methylation (DNAm) from cfDNA samples holds great promise due to the intrinsic characteristics of DNAm being more prevalent, pervasive, and cell- and tumor-type specific than genomics, for which established cfDNA assays already exist. Herein, we report on recent advances on experimental strategies for the analysis of DNAm in cfDNA samples. We describe the main steps of DNAm-based analysis workflows, including pre-analytics of cfDNA samples, DNA treatment, assays for DNAm evaluation, and methods for data analysis. We report on protocols, biomolecular techniques, and computational strategies enabling DNAm evaluation in the context of cfDNA analysis, along with practical considerations on input sample requirements and costs. We provide an overview on existing studies exploiting cell-free DNAm biomarkers for the detection and monitoring of cancer in early and advanced settings, for the evaluation of drug resistance, and for the identification of the cell-of-origin of tumors. Finally, we report on DNAm-based tests approved for clinical use and summarize their performance in the context of liquid biopsy.
Topics: Animals; Cell-Free Nucleic Acids; Computational Biology; DNA Methylation; Humans; Liquid Biopsy; Medical Oncology
PubMed: 33334040
DOI: 10.3390/biom10121677 -
Genetics in Medicine : Official Journal... Aug 2023HNRNPU haploinsufficiency is associated with developmental and epileptic encephalopathy 54. This neurodevelopmental disorder is characterized by developmental delay,...
PURPOSE
HNRNPU haploinsufficiency is associated with developmental and epileptic encephalopathy 54. This neurodevelopmental disorder is characterized by developmental delay, intellectual disability, speech impairment, and early-onset epilepsy. We performed genome-wide DNA methylation (DNAm) analysis in a cohort of individuals to develop a diagnostic biomarker and gain functional insights into the molecular pathophysiology of HNRNPU-related disorder.
METHODS
DNAm profiles of individuals carrying pathogenic HNRNPU variants, identified through an international multicenter collaboration, were assessed using Infinium Methylation EPIC arrays. Statistical and functional correlation analyses were performed comparing the HNRNPU cohort with 56 previously reported DNAm episignatures.
RESULTS
A robust and reproducible DNAm episignature and global DNAm profile were identified. Correlation analysis identified partial overlap and similarity of the global HNRNPU DNAm profile to several other rare disorders.
CONCLUSION
This study demonstrates new evidence of a specific and sensitive DNAm episignature associated with pathogenic heterozygous HNRNPU variants, establishing its utility as a clinical biomarker for the expansion of the EpiSign diagnostic test.
Topics: Humans; DNA Methylation; Epigenomics; Phenotype; Neurodevelopmental Disorders; Biomarkers
PubMed: 37120726
DOI: 10.1016/j.gim.2023.100871 -
BMC Biology Jan 2015In this Opinion article, we summarize how changes in DNA methylation occur during aging in mammals and discuss examples of how such events may contribute to the aging... (Review)
Review
In this Opinion article, we summarize how changes in DNA methylation occur during aging in mammals and discuss examples of how such events may contribute to the aging process. We explore mechanisms that could facilitate DNA methylation changes in a site-specific manner and highlight a model in which region-specific DNA hypermethylation during aging is facilitated in a competitive manner by destabilization of the Polycomb repressive complex.
Topics: Aging; Animals; Cellular Senescence; DNA Methylation; Disease; Humans; Organ Specificity; Stem Cells
PubMed: 25637097
DOI: 10.1186/s12915-015-0118-4 -
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 -
Genes Nov 2023Infertility affects a significant number of couples worldwide and its incidence is increasing. While assisted reproductive technologies (ART) have revolutionized the... (Review)
Review
Infertility affects a significant number of couples worldwide and its incidence is increasing. While assisted reproductive technologies (ART) have revolutionized the treatment landscape of infertility, a significant number of couples present with an idiopathic cause for their infertility, hindering effective management. Profiling the genome and transcriptome of infertile men and women has revealed abnormal gene expression. Epigenetic modifications, which comprise dynamic processes that can transduce environmental signals into gene expression changes, may explain these findings. Indeed, aberrant DNA methylation has been widely characterized as a cause of abnormal sperm and oocyte gene expression with potentially deleterious consequences on fertilization and pregnancy outcomes. This review aims to provide a concise overview of male and female infertility through the lens of DNA methylation alterations.
Topics: Pregnancy; Male; Humans; Female; DNA Methylation; Semen; Infertility; Epigenesis, Genetic; Reproductive Techniques, Assisted
PubMed: 38136954
DOI: 10.3390/genes14122132 -
Cells Jun 2020Colorectal carcinogenesis (CRC) is caused by the gradual long-term accumulation of both genetic and epigenetic changes. Recently, epigenetic alterations have been... (Review)
Review
Colorectal carcinogenesis (CRC) is caused by the gradual long-term accumulation of both genetic and epigenetic changes. Recently, epigenetic alterations have been included in the classification of the CRC molecular subtype, and this points out their prognostic impact. As epigenetic modifications are reversible, they may represent relevant therapeutic targets. DNA methylation, catalyzed by DNA methyltransferases (DNMTs), regulates gene expression. For many years, the deregulation of DNA methylation has been considered to play a substantial part in CRC etiology and evolution. Despite considerable advances in CRC treatment, patient therapy response persists as limited, and their profit from systemic therapies are often hampered by the introduction of chemoresistance. In addition, inter-individual changes in therapy response in CRC patients can arise from their specific (epi)genetic compositions. In this review article, we summarize the options of CRC treatment based on DNA methylation status for their predictive value. This review also includes the therapy outcomes based on the patient's methylation status in CRC patients. In addition, the current challenge of research is to develop therapeutic inhibitors of DNMT. Based on the essential role of DNA methylation in CRC development, the application of DNMT inhibitors was recently proposed for the treatment of CRC patients, especially in patients with DNA hypermethylation.
Topics: Colorectal Neoplasms; DNA Methylation; Humans
PubMed: 32599894
DOI: 10.3390/cells9061540 -
Trends in Genetics : TIG Jan 2024First identified in isogenic mice, metastable epialleles (MEs) are loci where the extent of DNA methylation (DNAm) is variable between individuals but correlates across... (Review)
Review
First identified in isogenic mice, metastable epialleles (MEs) are loci where the extent of DNA methylation (DNAm) is variable between individuals but correlates across tissues derived from different germ layers within a given individual. This property, termed systemic interindividual variation (SIV), is attributed to stochastic methylation establishment before germ layer differentiation. Evidence suggests that some putative human MEs are sensitive to environmental exposures in early development. In this review we introduce key concepts pertaining to human MEs, describe methods used to identify MEs in humans, and review their genomic features. We also highlight studies linking DNAm at putative human MEs to early environmental exposures and postnatal (including disease) phenotypes.
Topics: Humans; Animals; Mice; Epigenesis, Genetic; DNA Methylation; Phenotype; Genomics; Alleles
PubMed: 38000919
DOI: 10.1016/j.tig.2023.09.007 -
Nature Communications Dec 2022The interplay between histone modifications and DNA methylation drives the establishment and maintenance of the cellular epigenomic landscape, but it remains challenging...
The interplay between histone modifications and DNA methylation drives the establishment and maintenance of the cellular epigenomic landscape, but it remains challenging to investigate the complex relationship between these epigenetic marks across the genome. Here we describe a nanopore-sequencing-based-method, nanoHiMe-seq, for interrogating the genome-wide localization of histone modifications and DNA methylation from single DNA molecules. nanoHiMe-seq leverages a nonspecific methyltransferase to exogenously label adenine bases proximal to antibody-targeted modified nucleosomes in situ. The labelled adenines and the endogenous methylated CpG sites are simultaneously detected on individual nanopore reads using a hidden Markov model, which is implemented in the nanoHiMe software package. We demonstrate the utility, robustness and sensitivity of nanoHiMe-seq by jointly profiling DNA methylation and histone modifications at low coverage depths, concurrently determining phased patterns of DNA methylation and histone modifications, and probing the intrinsic connectivity between these epigenetic marks across the genome.
Topics: DNA Methylation; Histone Code; Nanopore Sequencing; Sequence Analysis, DNA; DNA; Epigenesis, Genetic
PubMed: 36566265
DOI: 10.1038/s41467-022-35650-2 -
Experimental Dermatology Aug 2021The observed incidence of psoriasis has been gradually increasing over time (J Am Acad Dermatol, 03, 2009, 394), but the underlying pathogenic factors have remained... (Review)
Review
The observed incidence of psoriasis has been gradually increasing over time (J Am Acad Dermatol, 03, 2009, 394), but the underlying pathogenic factors have remained unclear. Recent studies suggest the importance of epigenetic modification in the pathogenesis of psoriasis. Aberrant epigenetic patterns including changes in DNA methylation, histone modifications and non-coding RNA expression are observed in psoriatic skin. Reversing these epigenetic mechanisms has showed improvement in psoriatic phenotypes, making epigenetic therapy a potential avenue for psoriasis treatment. Here, we summarize relevant evidence for epigenetic dysregulation contributing to psoriasis susceptibility and pathogenesis, and the factors responsible for epigenetic modifications, providing directions for potential future clinical avenues.
Topics: DNA Methylation; Epigenesis, Genetic; Histones; Humans; Psoriasis
PubMed: 33756010
DOI: 10.1111/exd.14332