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Measuring an increased methylation of histons in sensitized lymphocytes is a method of detecting allergy against several allergens. Because of the short culture time it is adapted as an allergological rapidtest without high risk for microbial contamination.
Insects display exceptional phenotypic plasticity, which can be mediated by epigenetic modifications, including CpG methylation and histone modifications. In vertebrates, both are interlinked and CpG methylation is associated with gene repression. However, little is known about these regulatory systems in invertebrates, where CpG methylation is mainly restricted to gene bodies of transcriptionally active genes. A widely conserved mechanism involves the co-transcriptional deposition of H3K36 trimethylation and the targeted methylation of unmethylated CpGs by the de novo DNA methyltransferase DNMT3. However, DNMT3 has been lost multiple times in invertebrate lineages raising the question of how the links between CpG methylation, histone modifications and gene expression are affected by its loss. Here, we report the epigenetic landscape of Leptinotarsa decemlineata, a beetle species that has lost DNMT3 but retained CpG methylation. We combine RNA-seq, enzymatic methyl-seq and CUT&Tag to study gene expression, CpG methylation and patterns of H3K36me3 and H3K27ac histone modifications on a genome-wide scale. Despite the loss of DNMT3, H3K36me3 mirrors CpG methylation patterns. Together, they give rise to signature profiles for expressed and not expressed genes. H3K27ac patterns show a prominent peak at the transcription start site that is predictive of expressed genes irrespective of their methylation status. Our study provides new insights into the evolutionary flexibility of epigenetic modification systems that urge caution when generalizing across species.
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DNA methylation and histone modifications encode epigenetic information. Recently, major progress was made to measure either mark at a single-cell resolution; however, a method for simultaneous detection is lacking, preventing study of their interactions. Here, to bridge this gap, we developed scEpi2-seq. Our technique provides a readout of histone modifications and DNA methylation at the single-cell and single-molecule level. Application in a cell line with the FUCCI cell cycle reporter system reveals how DNA methylation maintenance is influenced by the local chromatin context. In addition, profiling of H3K27me3 and DNA methylation in the mouse intestine yields insights into epigenetic interactions during cell type specification. Differentially methylated regions also demonstrated independent cell-type regulation in addition to H3K27me3 regulation, which reinforces that CpG methylation acts as an additional layer of control in facultative heterochromatin.
The basolateral amygdala (BLA) serves in the evaluation of reward. However, the causal molecular substrates in the BLA necessary for reward seeking behaviour are largely unknown. Reward conditioning induces long-lasting changes in epienzymes in limbic areas, including the amygdala. The current study probed the role of histone arginine methylation as a novel epigenetic mechanism in neuropeptide Y (NPY) gene regulation in the BLA during reward and reinforcement. For reward conditioning, adult Wistar rats were trained to self-administer sucrose pellets in a nose-poke operant chamber. Reward conditioning increased protein arginine methyltransferase 4 (PRMT4) and NPY in the BLA. Moreover, after operant conditioning, histone arginine methylation (H3R17me2a) and PRMT4 occupancy at the NPY promoter were heightened. PRMT4 was predominantly colocalised in the nucleus of the NPY-expressing cells in the BLA. Intra-BLA administration of specific siRNA or inhibitor of PRMT4 after conditioning waned the nose-poke activity, which was further reinstated during the subsequent 5 days. These effects of PRMT4 repression were correlated with the NPY expression and H3R17me2a levels at the NPY promoter. Furthermore, NPY peptide administration after PRMT4 siRNA or inhibitor infusion in BLA restored the nose-poke activity. PRMT4 is known to interact with CREB-binding protein (CBP). Therefore, co-occupancy of PRMT4 and CBP resulted in heightened histone acetylation (H3K14ac) in the conditioned rats. The current study suggests a pivotal role of PRMT4-mediated histone arginine methylation in NPY gene expression in the amygdala necessary for the reward-seeking behaviour.
When isolated nuclei from 12-day-old rat brains were incubated with S-adenosyl-L-[methyl-3H]methionine, significant amounts of 3H-methyl were incorporated into lysyl residues in histones H3 and H4. About 0.024% of the total methylation sites on histone H3 and 0.013% of the sites on histone H4 were unmethylated at the time the nuclei were isolated. Methylation of these sites proceeded stepwise, progressing to a stable ratio of 0.93:1.0:0.17 for N epsilon-mono-, N epsilon-di-, and N epsilon-trimethyllysine in histone H3 and 0.19:1.0 for N epsilon-mono- and N epsilon-dimethyllysine in histone H4. The Km values of the enzyme for S-adenosyl-L-methionine were 11.5 +/- 1.1 micron and 12.5 +/- 1.3 micron with histones H3 and H4 as methyl acceptors, respectively. The Vmax values were 11.1 and 5.3 pmol of 3H-methyl incorporated/min/mg of histone H3 and H4, respectively. Since histone H3 contains 2 mol of N epsilon-methyllysine/mol and histone H4 contains 1 mol/mol, no difference in the overall rates of methylation can be deduced from the data. S-Adenosyl-L-homocysteine, one of the products of the reaction, was a competitive inhibitor with respect to S-adenosyl-L-methionine. The Ki values for S-adenosyl-L-homocysteine were 5.5 +/- 0.4 micron and 5.9 +/- 0.5 micron with histones H3 and H4 as methyl acceptors, respectively.
The histone H3K36-specific methyltransferase ASH1L plays a critical role in development and is frequently dysregulated in human diseases, particularly cancer. Here, we report on the biological functions of the C-terminal region of ASH1L encompassing a bromodomain (ASH1LBD), a plant homeodomain (ASH1LPHD) finger, and a bromo-adjacent homology (ASH1LBAH) domain, structurally characterize these domains, describe their mechanisms of action, and explore functional crosstalk between them. We find that ASH1LPHD recognizes H3K4me2/3, whereas the neighboring ASH1LBD and ASH1LBAH have DNA binding activities. The DNA binding function of ASH1LBAH is a driving force for the association of ASH1L with the linker DNA in the nucleosome, and the large interface with ASH1LPHD stabilizes the ASH1LBAH fold, merging two domains into a single module. We show that ASH1L is involved in embryonic stem cell differentiation and co-localizes with H3K4me3 but not with H3K36me2 at transcription start sites of target genes and genome wide, and that the interaction of ASH1LPHD with H3K4me3 is inhibitory to the H3K36me2-specific catalytic activity of ASH1L. Our findings shed light on the mechanistic details by which the C-terminal domains of ASH1L associate with chromatin and regulate the enzymatic function of ASH1L.
Olanzapine, an atypical antipsychotic agent, is widely used in treating psychotic disorders, yet its metabolic side effects remain a clinical concern. Emerging evidence suggests that dynamic alterations in histone methylation are implicated in olanzapine-induced hepatic lipid metabolic disorders. PHF2, a JmjC family histone demethylase mediating H3K9me2 demethylation, functions as a transcriptional repressor by regulating downstream targets. To elucidate PHF2's role in this process, we utilized an olanzapine-induced dyslipidemia rat model. ChIP-qPCR analysis demonstrated a significant reduction in dimethylated histone H3 lysine 9 (H3K9me2) on the promoters of lipogenic genes (Fasn, Acc1, Scd1) in the liver, accompanied by elevated nuclear expression of PHF2 in olanzapine-treated rats. Co-immunoprecipitation (Co-IP) assays revealed a physical interaction between PHF2 and ChREBP, a glucose-responsive lipogenic transcription factor. Olanzapine was found to enhance the formation of this complex. Overexpression of PHF2 led to upregulated protein levels of FASN/ACC1 and intracellular lipid accumulation, whereas knockdown of PHF2 using siRNA attenuated these effects. Notably, the upregulation of FASN/ACC1 expression induced by olanzapine was markedly diminished in PHF2-deficient AML12 cells via ChREBP-PHF2-mediated H3K9me2 demethylation. Additionally, olanzapine inhibited the nuclear translocation of FOXA2, a PHF2 transcriptional regulator, thereby augmenting PHF2 expression. These findings uncover a novel epigenetic mechanism underlying olanzapine-induced dyslipidemia, positioning the FOXA2-PHF2-ChREBP axis as a potential therapeutic target through modulation of hepatic histone methylation.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, with metastasis being the primary cause of its high mortality. The chromatin-binding protein, high mobility group nucleosome binding domain 1 (HMGN1), has been implicated in tumour progression, but its specific role and mechanism in HCC metastasis remain unclear. This study investigates the function of HMGN1 and its potential as a therapeutic target. Analysis of patient samples confirms an upregulation of HMGN1 in HCC tissues, correlating with advanced disease and poor prognosis. Functional assays demonstrate that HMGN1 promotes HCC metastasis in vitro and in vivo. Mechanistically, integrated RNA sequencing and chromatin immunoprecipitation sequencing analyses reveal that HMGN1 binds to the promoter of RAS-like proto-oncogene B (RALB) gene, recruiting the repressive histone mark H3K9me2 to epigenetically silence its transcription and drive metastasis. Therapeutically, a nanoparticle delivery system for siRNA against HMGN1 effectively silences its expression and inhibits metastasis in orthotopic liver xenograft tumour models. Our findings establish HMGN1 as a key epigenetic driver of HCC metastasis and highlight siRNA-nanoparticle targeting of HMGN1 as a promising precision therapeutic strategy.
Alzheimer's disease (AD) is a complex neurodegenerative disorder in which most risk variants are noncoding and are enriched at gene regulatory regions, implicating epigenetic mechanisms as central mediators of disease pathogenesis. For most of the history of AD epigenetics research, bulk tissue analysis has dominated, obscuring the fundamentally distinct epigenomic landscapes of individual brain cell types and masking cell-type-specific contributions to disease. Advances in single-cell and single-nucleus sequencing, fluorescence-activated nuclei sorting and multiplexed epigenomic platforms have transformed this landscape, enabling cell-type-resolved profiling of chromatin accessibility, DNA methylation, histone modifications and transcription across the major neuronal, glial and neurovascular populations of the human brain. Here, we review these advances, structured around the argument that cell-type resolution is not a methodological refinement but a conceptual necessity. We describe the distinct epigenomic programs disrupted in neurons, microglia, astrocytes, oligodendrocytes and neurovascular cells in AD, highlighting how each cell type responds to pathology. We discuss the discovery of epigenomic erosion, the progressive loss of cell-type-specific epigenomic identity across virtually all brain cell populations as AD advances, as a unifying disease mechanism linking chromatin dysregulation to cognitive decline. Finally, we identify critical gaps in current knowledge, including the near-complete absence of cell-type-resolved histone modification and DNA methylation data for most brain cell types, the underrepresentation of rare populations in standard preparations and the untapped potential of metabolic acylation marks as indicators of the epigenome-metabolism interface in neurodegeneration.
Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome characterized by persistent oxidative stress and maladaptive immune responses, rather than a single disease entity. Oxidative stress not only damages lung tissue but also reprograms immune cells through both classical epigenetic mechanisms (DNA methylation, histone modifications) and epitranscriptomic regulation (m6A RNA methylation), shaping disease endotypes and treatment resistance. This review presents an integrated framework in which redox signals dynamically reshape the epigenetic and epitranscriptomic landscape, thereby locking immune cells into pathogenic states. Metabolic intermediates (S-adenosylmethionine, α-ketoglutarate, succinate, NAD+) serve as critical nodes that connect immunometabolism to both classical epigenetic enzymes and the m6A machinery, thereby linking redox status to RNA fate. Using NETosis as a paradigm, we illustrate how oxidative-epigenetic-metabolic loops sustain neutrophilic inflammation and resolution failure. Finally, we outline a treatable traits framework that integrates these mechanistic insights into precision combination therapies. This conceptual roadmap aims to shift COPD management from symptom control toward durable, mechanism-driven disease modification.
Jarid2 is a reported component of three lysine methyltransferase complexes, polycomb repressive complex 2 (PRC2) that methylates histone 3 lysine 27 (H3K27), and GLP-G9a and SETDB1 complexes that methylate H3K9. Here we show that Jarid2 is upregulated upon TCR stimulation and during positive selection in the thymus. Mice lacking Jarid2 in T cells display an increase in the frequency of IL-4-producing promyelocytic leukemia zinc finger (PLZF)(hi) immature invariant natural killer T (iNKT) cells and innate-like CD8(+) cells; Itk-deficient mice, which have a similar increase of innate-like CD8(+) cells, show blunted upregulation of Jarid2 during positive selection. Jarid2 binds to the Zbtb16 locus, which encodes PLZF, and thymocytes lacking Jarid2 show increased PLZF and decreased H3K9me3 levels. Jarid2-deficient iNKT cells perturb Th17 differentiation, leading to reduced Th17-driven autoimmune pathology. Our results establish Jarid2 as a novel player in iNKT cell maturation that regulates PLZF expression by modulating H3K9 methylation.
Epigenetic modifications such as histone methylation permit change in chromatin structure without accompanying change in the underlying genomic sequence. A number of studies in animal models have shown that dysregulation of various components of the epigenetic machinery causes cognitive deficits at the behavioral level, suggesting that proper epigenetic control is necessary for the fundamental processes of learning and memory. Histone H3 lysine K4 (H3K4) methylation comprises one component of such epigenetic control, and global levels of this mark are increased in the hippocampus during memory formation. Modifiers of H3K4 methylation are needed for memory formation, shown through animal studies, and many of the same modifiers are mutated in human cognitive diseases. Indeed, all of the known H3K4 methyltransferases and four of the known six H3K4 demethylases have been associated with impaired cognition in a neurologic or psychiatric disorder. Cognitive impairment in such patients often manifests as intellectual disability, consistent with a role for H3K4 methylation in learning and memory. As a modification quintessentially, but not exclusively, associated with transcriptional activity, H3K4 methylation provides unique insights into the regulatory complexity of writing, reading, and erasing chromatin marks within an activated neuron. The following review will discuss H3K4 methylation and connect it to transcriptional events required for learning and memory within the developed nervous system. This will include an initial discussion of the most recent advances in the developing methodology to analyze H3K4 methylation, namely mass spectrometry and deep sequencing, as well as how these methods can be applied to more deeply understand the biology of this mark in the brain. We will then introduce the core enzymatic machinery mediating addition and removal of H3K4 methylation marks and the resulting epigenetic signatures of these marks throughout the neuronal genome. We next foray into the brain, discussing changes in H3K4 methylation marks within the hippocampus during memory formation and retrieval, as well as the behavioral correlates of H3K4 methyltransferase deficiency in this region. Finally, we discuss the human cognitive diseases connected to each H3K4 methylation modulator and summarize advances in developing drugs to target them.
How cytoplasmic regulators control nuclear events in mammalian oocytes and early embryos remains largely enigmatic. We previously identified a subcortical maternal complex (SCMC) that specifically resides in the cytoplasm of mammalian oocytes and early embryos but is also involved in nuclear events. Nevertheless, how the cytoplasmic SCMC exerts its role in nuclear processes remains unknown. In this study, we unveil SPIN1, a histone methylation reader, as a novel member of the SCMC. The SCMC component FILIA tightly regulates the expression and cytoplasmic localization of SPIN1 through direct interaction. When the expression of FILIA is decreased because of genetic mutations of SCMC genes, SPIN1 expression is dramatically reduced but the residual SPIN1 translocates into the nucleus. The abnormal nuclear presence of SPIN1 impairs H3K4me3 reprogramming, zygotic genome activation and physiological embryonic development. Inhibiting the interaction between SPIN1 and H3K4me3 partially rescues the abnormal phenotype in FILIA-null embryos. Mechanistically, SPIN1 partially perturbs the demethylation process by competing with KDM5B for binding to H3K4me3. Collectively, our work highlights the complexity of the mammalian SCMC and oocyte-to-embryo transition, revealing an intricate regulatory mechanism that facilitates the smooth progression of this process.
The mealybug Pseudococcus viburni is a plant-feeding insect with a non-Mendelian genetic system known as paternal genome elimination (PGE). In PGE, males eliminate their paternally inherited chromosomes during meiosis, transmitting only the maternal genome to the next generation. This involves genome-wide imprinting, where paternal chromosomes are heterochromatinised in embryogenesis and throughout adulthood. In this species, a non-essential B chromosome can escape paternal genome elimination, thereby enhancing its transmission rate to the next generation. Previous studies show that the B chromosome escapes elimination by changing its chromatin compaction during meiosis to resemble that of maternal chromosomes. Although the exact mechanism underlying this change is poorly understood. Here we investigated histone methylation and acetylation modifications, as well as the Heterochromatin Protein 1 (HP1), to characterise differences between maternal, paternal and B chromosomes during male meiosis of P. viburni. Maternal and paternal chromosomes show distinct histone modification patterns, with marks associated with euchromatin present on maternal chromosomes and marks associated with heterochromatin present on paternal chromosomes. We then identified key histone modification changes that coincide with chromatin remodelling of the B chromosome, which allows it to segregate with maternal chromosomes. In addition, we showed that these chromatin modifications occur regardless of the parental origin of the B chromosome. Overall, our findings support the role of histone modifications for proper chromosome segregation during meiosis in mealybugs and provide insight into the mechanisms by which the B chromosome exploits PGE for its preferential transmission.
Triple Negative Breast Cancer (TNBC), an aggressive type of Breast Cancer (BC) characterized by the loss of expression of Estrogen Receptor (ER), Progesterone Receptor (PR), and Human Epidermal growth factor Receptor 2 (HER2) protein. TNBC is quite heterogenous in nature with limited available therapeutic options due to the lack of defined molecular targets. Epigenetic abnormalities have been implicated in the onset, progression, immune escape, and resistance to treatment in TNBC. Important epigenetic modulations, include DNA methylation, histone lactylation, histone modifications, and chromatin remodeling. Global hypomethylation contributes to genomic instability, while promoter hypermethylation inhibits tumor suppressor genes, by dysregulating their expression, thereby promoting uncontrolled proliferation, EMT, metastasis, and immune evasion in TNBC. Targeting epigenetic modulators, have the potential to develop novel therapeutic interventions have been developed and being explored. These epidrugs have proven to be effective in preclinical and clinical trials when used in combination with chemotherapy, immunotherapy, or targeted therapy, reducing drug resistance and aberrant proliferation. Despite of the advancements, challenges like target specificity, precise biomarkers and treatment related toxicity are the major hurdles. The review comprehensively summarized the important epigenetic alterations as well as novel treatment strategies with potential clinical applications in TNBC.
Human biology and diseases are the result of constantly evolving processes within an intricately complex molecular network of interactions, such as epigenetic regulation. Epigenetics refers to heritable changes in gene expression that occur without alterations to the underlying DNA sequence. These changes, driven by mechanisms such as DNA methylation, histone modifications, and noncoding RNAs, play critical roles in regulating chromatin structure and gene activity. Epigenetic regulation offers valuable insights into biological systems, and when integrated with sophisticated analyses, it enables us to gain insights into gene regulation and cellular behavior. Here, we describe an artificial intelligence (AI)-based model that is capable of generating 3-dimensional (3D) heterogeneous network by integrating multimodal data for the functional prediction of epigenetic mechanisms, emphasizing its applications in medicine, developmental biology, and personalized therapeutics. Heterogeneous networks in biology are powerful tools for understanding the complex interactions and interdependencies within biological systems. Key advancements in AI and multiomics data integration have propelled this field, offering new insights into disease mechanisms, biomarker discovery, and therapeutic interventions.
Dilated cardiomyopathy (DCM) is a nonischemic heart muscle disease characterized by impaired contractility, cardiac dilation, and heart failure, with both genetic and nongenetic causes. Emerging evidence highlights epigenetic mechanisms, including deoxyribonucleic acid methylation, histone modifications, chromatin remodeling, and noncoding RNAs, as critical regulators of gene expression in DCM pathogenesis. This article explores familial DCM linked to pathogenic variants in genes like lamin A/C and titin, as well as nongenetic forms such as diabetic and autoimmune DCM. By summarizing recent discoveries, it highlights the epigenetic factors in bridging genetic and environmental influences, offering potential biomarkers and therapeutic targets for improved DCM management.