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At least 307 records · Page 17Linked to original sources
PubMed2026

Recurrent mechanisms of biallelic epigenetic inactivation reveal new putative tumour suppressor genes in prostate cancer.

The inactivation of tumour suppressor genes is a key step in cancer development, and is usually achieved by homozygous loss. In prostate cancer, however, large genomic regions are often hemizygously lost, which complicates the identification of putative tumour suppressors in these regions. Here, we develop Epi2Hit, an integrative computational method that leverages whole genome sequencing, epigenomic profiling and gene expression to identify biallelic inactivation of tumour suppressor genes involving DNA methylation of promoter and enhancer regions of one allele and genomic loss of the other allele. We apply Epi2Hit to a cohort of 2,021 prostate cancers to discover tumour suppressor genes. In particular, we identify epigenetic biallelic inactivation of ZFHX3 at a recurrence level similar to TP53. Biallelic inactivation of ZFHX3, a transcriptional repressor, leads to upregulation of oncogenes, including MYC and a shorter time to metastasis. Finally, we provide evidence that epigenetic silencing as 2nd hit is particularly enriched in regions with nearby essential genes, precluding homozygous loss.

Prostatic Neoplasms↗
PubMed2026

Genome-wide DNA methylation analysis revealed epigenetic mechanism underlying end-stage renal disease.

End-stage renal disease (ESRD) remains a major clinical challenge with high morbidity and mortality, and its molecular mechanisms, particularly those shared among diverse primary kidney diseases during progression to ESRD, have not been studied. Here we conduct a large-scale two-stage epigenome-wide association study of ESRD in two independent cohorts consisting of 704 controls and 1031 ESRD cases. We identify 52 ESRD-associated differentially methylated CpG positions (ESRD DMPs) showing consistent association between the two cohorts and across diverse kidney diseases, implicating 144 candidate genes enriched in inflammatory and immune pathways. Five of the 52 DMPs are associated with ESRD complications, and seven with renal function decline in early-stage chronic kidney disease, demonstrating their potential as prognostic biomarkers for ESRD and its complications. Our findings highlight inflammation, immune dysregulation, and renal fibrosis as shared epigenetic drivers of ESRD progression, and identify biomarkers with potential utility for risk stratification and therapeutic intervention.

Humans↗
PubMed2026

Epigenetic-epitranscriptomic crosstalk through TaHAG1-TaNSUN2 coordinates thermotolerance in wheat.

High temperature is a primary abiotic stress that severely constrains crop productivity. Deciphering the regulatory pathways underlying heat responses is essential for breeding heat-tolerant crops with stable yields. Although both epigenetic and epitranscriptomic regulations are involved in plant heat adaptation, their mechanistic interplay remains unclear. Here, integrated epigenomic (H3K9Ac/H3K14Ac) and transcriptomic profiling under heat stress identifies the mRNA m⁵C methyltransferase TaNSUN2 as a key regulator of thermotolerance in wheat. We demonstrate that TaNSUN2 is transcriptionally activated by the histone acetyltransferase TaHAG1, which deposits H3K9Ac at the TaNSUN2 promoter and transcription start site. This recruitment is facilitated by the transcription factors TaE2F1 and TaDP1, which interact with TaHAG1 to form a functional complex. Functional assays revealthat TaNSUN2 operates downstream of TaHAG1 and enhances thermotolerance through m⁵C‑dependent mRNA methylation and stabilization of transcripts involved in chloroplast organization. Furthermore, field trials show that TaNSUN2-overexpressing lines exhibit higher grain yield under normal conditions and reduced yield loss under heat stress. Our findings elucidate an integrated regulatory network linking histone acetylation to RNA m⁵C methylation in heat stress adaptation, providing promising targets for molecular breeding of heat‑resilient wheat.

Triticum↗
PubMed2026

Gene regulatory mechanisms downstream of DNA methylation.

Cytosine DNA methylation is a conserved epigenetic modification that regulates gene expression, represses transposable elements and maintains genome stability across diverse eukaryotes. Although major advances have uncovered the pathways involved in the establishment, maintenance and removal of DNA methylation, the downstream mechanisms by which this mark influences transcriptional programmes and shapes chromatin structure are less well understood. Here, we review how specialized reader proteins and transcription factors interpret DNA methylation to preserve methylation patterns, recruit effector complexes, regulate chromatin accessibility and interact with parallel epigenetic systems to mediate transcriptional silencing and activation across mammals and plants. We highlight that robust transcriptional and epigenetic states emerge from overlapping, layered and partially redundant DNA methylation-dependent mechanisms. Together, these insights provide a framework for understanding how DNA methylation shapes the epigenome to regulate development, differentiation and disease progression.

Journal Article↗
PubMed2025

Evolutionary fingerprints of epithelial-to-mesenchymal transition.

Mesenchymal plasticity has been extensively described in advanced epithelial cancers; however, its functional role in malignant progression is controversial1-5. The function of epithelial-to-mesenchymal transition (EMT) and cell plasticity in tumour heterogeneity and clonal evolution is poorly understood. Here we clarify the contribution of EMT to malignant progression in pancreatic cancer. We used somatic mosaic genome engineering technologies to trace and ablate malignant mesenchymal lineages along the EMT continuum. The experimental evidence clarifies the essential contribution of mesenchymal lineages to pancreatic cancer evolution. Spatial genomic analysis, single-cell transcriptomic and epigenomic profiling of EMT clarifies its contribution to the emergence of genomic instability, including events of chromothripsis. Genetic ablation of mesenchymal lineages robustly abolished these mutational processes and evolutionary patterns, as confirmed by cross-species analysis of pancreatic and other human solid tumours. Mechanistically, we identified that malignant cells with mesenchymal features display increased chromatin accessibility, particularly in the pericentromeric and centromeric regions, in turn resulting in delayed mitosis and catastrophic cell division. Thus, EMT favours the emergence of genomic-unstable, highly fit tumour cells, which strongly supports the concept of cell-state-restricted patterns of evolution, whereby cancer cell speciation is propagated to progeny within restricted functional compartments. Restraining the evolutionary routes through ablation of clones capable of mesenchymal plasticity, and extinction of the derived lineages, halts the malignant potential of one of the most aggressive forms of human cancer.

Animals↗
PubMed2026

Subnuclear genome compartmentalization controls bivalent chromatin activity.

The nuclear genome is spatially organized into a three-dimensional architecture by physical association of large chromosomal domains with subnuclear compartments including the nuclear lamina at the radial periphery and nuclear speckles within the nucleoplasm1-5. However, how higher-order spatial genome architecture regulates human development has been overlooked, and the interplay between chromatin state and subnuclear genome compartmentalization is poorly understood. Here we generate high-resolution maps of genomic interactions with the lamina and speckles in cells of the neurogenic lineage isolated from mid-gestational human cortex, identifying an intimate association between subnuclear genome compartmentalization, chromatin state and transcription. During cortical neurogenesis, subnuclear genome compartmentalization is extensively remodelled, relocating hundreds of neuronal genes from the lamina to speckles, including key neurodevelopmental genes bivalent for trimethylation of histone H3 at Lys27 (H3K27me3) and Lys4 (H3K4me3). At the lamina, bivalent genes have exceptionally low expression, and relocation to speckles enhances resolution of bivalent chromatin to H3K4me3 monovalency and increases transcription more than eightfold. We further demonstrate that proximity to the nuclear periphery-not the presence of H3K27me3-maintains the lowly expressed, poised state of bivalent genes embedded in the lamina. We find that the repressive environment of the lamina is associated with spatial segregation of the transcriptional elongation machinery from the nuclear periphery. Our results establish a paradigm in which knowing the spatial location of a gene is necessary for understanding its epigenomic regulation.

Humans↗
PubMed2026

DNA methylation profiles of quail blood cells by whole-genome bisulfite and Oxford Nanopore sequencing.

Whole Genome Bisulfite Sequencing (WGBS) has been the gold standard DNA methylation mapping and quantification for over a decade. Oxford Nanopore Technologies (ONT) sequencing directly measures nucleotide modifications. In this study, we have compared DNA methylation levels (5-methylcytosine) at CpG sites in the quail genome using WGBS and ONT. Samples were collected to investigate transgenerational DNA methylation changes in Japanese quail following ancestral exposure to a phytoestrogen. Blood samples from 24 third-generation (G3) individuals-descendants of either treated or untreated ancestors-were sequenced after bisulfite conversion. Both methods revealed broadly consistent methylation patterns. ONT reads covered more CpG sites and detected a higher number of differentially methylated cytosines (DMCs). Principal component analyses showed that both sex and ancestral treatment groups accounted for a portion of the observed epigenetic variation, for both technologies. Strong concordance between WGBS and ONT results supports the reliability of ONT sequencing for epigenomic research, including in quails. These data pave the way for further investigation into whether genistein induces epigenetic changes for several generations.

Animals↗
PubMed2018

Chromatin architecture changes and DNA replication fork collapse are critical features in cryopreserved cells that are differentially controlled by cryoprotectants.

In this work, we shed new light on the highly debated issue of chromatin fragmentation in cryopreserved cells. Moreover, for the first time, we describe replicating cell-specific DNA damage and higher-order chromatin alterations after freezing and thawing. We identified DNA structural changes associated with the freeze-thaw process and correlated them with the viability of frozen and thawed cells. We simultaneously evaluated DNA defects and the higher-order chromatin structure of frozen and thawed cells with and without cryoprotectant treatment. We found that in replicating (S phase) cells, DNA was preferentially damaged by replication fork collapse, potentially leading to DNA double strand breaks (DSBs), which represent an important source of both genome instability and defects in epigenome maintenance. This induction of DNA defects by the freeze-thaw process was not prevented by any cryoprotectant studied. Both in replicating and non-replicating cells, freezing and thawing altered the chromatin structure in a cryoprotectant-dependent manner. Interestingly, cells with condensed chromatin, which was strongly stimulated by dimethyl sulfoxide (DMSO) prior to freezing had the highest rate of survival after thawing. Our results will facilitate the design of compounds and procedures to decrease injury to cryopreserved cells.

Cell Survival↗
PubMed2022

A multi-omic analysis of MCF10A cells provides a resource for integrative assessment of ligand-mediated molecular and phenotypic responses.

The phenotype of a cell and its underlying molecular state is strongly influenced by extracellular signals, including growth factors, hormones, and extracellular matrix proteins. While these signals are normally tightly controlled, their dysregulation leads to phenotypic and molecular states associated with diverse diseases. To develop a detailed understanding of the linkage between molecular and phenotypic changes, we generated a comprehensive dataset that catalogs the transcriptional, proteomic, epigenomic and phenotypic responses of MCF10A mammary epithelial cells after exposure to the ligands EGF, HGF, OSM, IFNG, TGFB and BMP2. Systematic assessment of the molecular and cellular phenotypes induced by these ligands comprise the LINCS Microenvironment (ME) perturbation dataset, which has been curated and made publicly available for community-wide analysis and development of novel computational methods ( synapse.org/LINCS_MCF10A ). In illustrative analyses, we demonstrate how this dataset can be used to discover functionally related molecular features linked to specific cellular phenotypes. Beyond these analyses, this dataset will serve as a resource for the broader scientific community to mine for biological insights, to compare signals carried across distinct molecular modalities, and to develop new computational methods for integrative data analysis.

Epidermal Growth Factor↗
PubMed2026

Cell-specific DNA methylation in human alpha and beta cells regulates gene expression in type 2 diabetes.

Epigenome-wide studies of pancreatic islets provide valuable insights into type 2 diabetes (T2D) but lack methylomes from individual cell types. Here we show changes to alpha and beta cell-specific methylomes and transcriptomes from people with or without T2D, using whole-genome bisulfite sequencing and RNA sequencing. We discover 22,544 differentially methylated regions annotated to 7,975 genes in alpha versus beta cells, such as INS, GCG, PDX1 and PCSK1, with ~50% showing differential expression. CRISPR-dCas9-DNMT3A-based epigenetic editing increases INS and TH DNA methylation, while CRISPR-dCas9-TET1-based editing decreases GCG methylation, each altering INS, TH or GCG expression and content in beta cells. Pre-T2D/T2D-associated differentially methylated regions in alpha and beta cells overlap 12-18% of T2D-associated genome-wide association study candidates. Additionally, ONECUT2 is epigenetically upregulated in beta cells from people with pre-T2D/T2D and elevated in male Goto-Kakizaki rat islets. ONECUT2 overexpression in beta cells/islets downregulates gene sets impacting insulin secretion and glucose homeostasis, and reduces mitochondrial activity, ATP/ADP ratio and insulin secretion. We also provide 'alpha-beta-methylome' ( https://alpha-beta-methylome.serve.scilifelab.se/app/alpha-beta-methylome/ ), a resource exploring T2D, age and sex associations on methylation, highlighting cell-specific epigenetic regulation and dysfunctions contributing to T2D.

Humans↗
PubMed2024

Kick-starting the zygotic genome: licensors, specifiers, and beyond.

Zygotic genome activation (ZGA), the first transcription event following fertilization, kickstarts the embryonic program that takes over the control of early development from the maternal products. How ZGA occurs, especially in mammals, is poorly understood due to the limited amount of research materials. With the rapid development of single-cell and low-input technologies, remarkable progress made in the past decade has unveiled dramatic transitions of the epigenomes, transcriptomes, proteomes, and metabolomes associated with ZGA. Moreover, functional investigations are yielding insights into the key regulators of ZGA, among which two major classes of players are emerging: licensors and specifiers. Licensors would control the permission of transcription and its timing during ZGA. Accumulating evidence suggests that such licensors of ZGA include regulators of the transcription apparatus and nuclear gatekeepers. Specifiers would instruct the activation of specific genes during ZGA. These specifiers include key transcription factors present at this stage, often facilitated by epigenetic regulators. Based on data primarily from mammals but also results from other species, we discuss in this review how recent research sheds light on the molecular regulation of ZGA and its executors, including the licensors and specifiers.

Animals↗
PubMed2003

Frequent epigenetic inactivation of the SLIT2 gene in gliomas.

The SLIT family of genes consists of large extracellular matrix-secreted and membrane-associated glycoproteins. The Slits (Slit1-3) are ligands for the repulsive guidance receptors, the robo gene family. The Slit-Robo interactions mediate the repulsive cues on axons and growth cones during neural development. In a recent report, we demonstrated that promoter region CpG island of human SLIT2 was frequently hypermethylated in lung, breast and colorectal tumours and the silenced gene transcript suppressed the malignant phenotype in in vitro assays. In this report we undertook epigenetic, genetic and expression analysis of SLIT2 gene in a large series of gliomas and glioma cell lines. Promoter region CpG island of SLIT2 was found to be methylated in 71% (5/7) of glioma cell lines and was unmethylated in five DNA samples from normal brain tissues. The hypermethylation of the SLIT2 promoter region in glioma cell lines correlated with loss of expression and treatment with the demethylating agent 5-aza-2'-deoxycytidine reactivated SLIT2 gene expression. In primary gliomas, SLIT2 was methylated in 59% (37/63) of tumours analysed. In addition, SLIT2 expression was downregulated in methylated gliomas relative to unmethylated tumour samples, as demonstrated by quantitative real-time RT-PCR. Loss of heterozygosity analysis revealed that SLIT2 methylated gliomas retained both alleles of a microsatellite marker within 100 kb of the SLIT2 gene at 4p15.2. Exogenous expression of SLIT2 in a glioma cell line that was heavily methylated for SLIT2 decreased in vitro colony formation. Our data indicate that SLIT2 is frequently inactivated by promoter region CpG island hypermethylation in gliomas and may be a good candidate for a glioma tumour suppressor gene (TSG) located at 4p15.2. Furthermore, our data suggest that a detailed analysis of both the cancer genome and epigenome will be required to identify key TSGs involved in glioma development.

Antimetabolites, Antineoplastic↗
PubMed2006

Nuclear architecture in the light of gene expression and cell differentiation studies.

It is evident that primary DNA sequences, that define genomes, are responsible for genome functions. However, the functional properties of chromatin are additionally regulated by heritable modifications known as epigenetic factors and, therefore, genomes should be also considered with respect to their 'epigenomes'. Nucleosome remodelling, DNA methylation and histone modifications are the most prominent epigenetic changes that play fundamental roles in the chromatin-mediated control of gene expression. Another important nuclear feature with functional relevance is the organization of mammalian chromatin into distinct chromosome territories which are surrounded by the interchromatin compartment that is necessary for transport of regulatory molecules to the targeted DNA. The inner structure of the chromosome territories, as well as the arrangement of the chromosomes within the interphase nuclei, has been found to be non-randomly organized. Therefore, a specific nuclear arrangement can be observed in many cellular processes, such as differentiation and tumour cell transformation.

Cell Differentiation↗
PubMed2006

Chromatin-remodelling factors and the maintenance of transcriptional states through DNA replication.

At the replication fork, nucleosomes, transcription factors and RNA polymerases are stripped off the DNA, the DNA double strands are unzipped and DNA methylation marks may be erased. Therefore DNA replication is both a 'curse' and 'bliss' for the epigenome, as it disrupts its stability by causing chromatin perturbations, yet it offers an opportunity to initiate changes in chromatin architecture and gene expression patterns, especially during development. Thus the DNA replication site is a critical point for regulation. It has become apparent that there is a close functional relationship between those factors that regulate transcriptional competence and the DNA replication programme. In this review we discuss novel insights into how chromatin-remodelling factors at replication sites are involved in both the maintenance and regulation of transcriptional states.

Binding Sites↗
PubMed2005

[Epigenetics as an aspect of post-genomics].

A cell transmits to its progeny the activity level of many of its genes, not just their sequence. Just like the sequence may vary through a mutation, the gene activity level may change through an "epimutation" (an epigenetic modification) which is heritable and does not entail any concomitant genetic alteration. An epimutation can have important phenotypic consequences, that eventually survive to the loss of the environmental conditions that triggered it. For instance, epimutations are responsible for the divergence between a neuron and an epithelial cell that both come from the same egg and contain the same genome complement. This phenotypic difference is much larger than the one between the neurons from two animal species with dissimilar genotypes, thereby underlining the importance of epimutations. Tradition opposes the genetic and epigenetic visions, the latter being often adequated to the DNA methylation phenomenon. However, epimutations display a rich spectrum of modes that can all fit in a unique reference system based on correlated chemical, spatial and temporal scales. This reference system allows the integration of purely genetic mutations at one of its ends, thus paving the way to a new, gradual vision that encompasses the genome and the epigenome. At the other end can be found two types of epimutations that are both wide-ranging in space and rapid in producing phenotypic alterations. Firstly, long-range rearrangements of the three-dimensional structure of the chromosome may influence gene expression in an heritable fashion. Such rearrangements seem to result from the collective dynamics of DNA-related activities, particularly transcription. Lastly, heritable regulatory states, e.g. a differentiated state that results from tipping a regulatory "toggle switch", involve components that are distributed throughout the nucleus or the cytoplasm, and possibly all the way to cell confines.

Epigenesis, Genetic↗
PubMed2024

A time-resolved single-cell roadmap of the logic driving anterior neural crest diversification from neural border to migration stages.

Neural crest cells exemplify cellular diversification from a multipotent progenitor population. However, the full sequence of early molecular choices orchestrating the emergence of neural crest heterogeneity from the embryonic ectoderm remains elusive. Gene-regulatory-networks (GRN) govern early development and cell specification toward definitive neural crest. Here, we combine ultradense single-cell transcriptomes with machine-learning and large-scale transcriptomic and epigenomic experimental validation of selected trajectories, to provide the general principles and highlight specific features of the GRN underlying neural crest fate diversification from induction to early migration stages using Xenopus frog embryos as a model. During gastrulation, a transient neural border zone state precedes the choice between neural crest and placodes which includes multiple converging gene programs. During neurulation, transcription factor connectome, and bifurcation analyses demonstrate the early emergence of neural crest fates at the neural plate stage, alongside an unbiased multipotent-like lineage persisting until epithelial-mesenchymal transition stage. We also decipher circuits driving cranial and vagal neural crest formation and provide a broadly applicable high-throughput validation strategy for investigating single-cell transcriptomes in vertebrate GRNs in development, evolution, and disease.

Animals↗
PubMed2024

Long noncoding RNA LIRIL2R modulates FOXP3 levels and suppressive function of human CD4+ regulatory T cells by regulating IL2RA.

Regulatory T cells (Tregs) are central in controlling immune responses, and dysregulation of their function can lead to autoimmune disorders or cancer. Despite extensive studies on Tregs, the basis of epigenetic regulation of human Treg development and function is incompletely understood. Long intergenic noncoding RNAs (lincRNA)s are important for shaping and maintaining the epigenetic landscape in different cell types. In this study, we identified a gene on the chromosome 6p25.3 locus, encoding a lincRNA, that was up-regulated during early differentiation of human Tregs. The lincRNA regulated the expression of interleukin-2 receptor alpha (IL2RA), and we named it the lincRNA regulator of IL2RA (LIRIL2R). Through transcriptomics, epigenomics, and proteomics analysis of LIRIL2R-deficient Tregs, coupled with global profiling of LIRIL2R binding sites using chromatin isolation by RNA purification, followed by sequencing, we identified IL2RA as a target of LIRIL2R. This nuclear lincRNA binds upstream of the IL2RA locus and regulates its epigenetic landscape and transcription. CRISPR-mediated deletion of the LIRIL2R-bound region at the IL2RA locus resulted in reduced IL2RA expression. Notably, LIRIL2R deficiency led to reduced expression of Treg-signature genes (e.g., FOXP3, CTLA4, and PDCD1), upregulation of genes associated with effector T cells (e.g., SATB1 and GATA3), and loss of Treg-mediated suppression.

Humans↗
PubMed2026

AML1-ETO hijacks a distal enhancer of NAT10 to reprogram glutathione metabolism and sustain leukemia stem cell stemness.

Chromosomal translocations produce oncogenic fusion proteins such as AML1-ETO, which predominantly occupy gene promoters to induce transcriptional reprogramming in leukemia stem cells (LSCs), consequently driving the pathogenesis of t(8;21) acute myeloid leukemia (AML). However, whether AML1-ETO is recruited to additional regulatory DNA elements to orchestrate oncogenic gene expression programs has not been fully addressed. Here, we define AML1-ETO and H3K27ac CUT&Tag landscapes in primary t(8;21) AML CD34+ cells and t(8;21) AML cell lines, revealing AML1-ETO binding at a distal enhancer of the RNA N4-acetylcytidine (ac4C) writer N-acetyltransferase 10 (NAT10), thereby driving its transcriptional activation. Genetic ablation or pharmacological inhibition of NAT10 restricted the survival and self-renewal of LSCs in primary t(8;21) AML CD34+ cells, as well as in a retroviral AML1-ETO9a-driven t(8;21) AML mouse model, establishing NAT10 as a potential therapeutic vulnerability. Mechanistically, NAT10 is recruited to glutathione S-transferase omega 2 (GSTO2) mRNA to catalyze ac4C modification, thereby enhancing transcript stability and reprogramming glutathione metabolism, as demonstrated by ac4C profiling, RNA immunoprecipitation (RIP), and dCas13b-NAT10-based analyses. Silencing of GSTO2 in primary t(8;21) AML CD34+ cells decreased intracellular reduced glutathione (GSH) levels and compromised LSC survival and self-renewal, whereas GSTO2 overexpression or GSH supplementation largely rescued LSC maintenance following NAT10 loss. Collectively, these findings enrich and extend the understanding of AML1-ETO regulatory programs by linking distal enhancer activity to a NAT10-GSTO2 ac4C-GSH axis that integrates epigenomic, posttranscriptional, and metabolic reprogramming to sustain LSC stemness, highlighting this circuit as a potential therapeutic vulnerability in t(8;21) AML.

Humans↗