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Results for “epigenetic modification”

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PubMed2025

High Hcy regulates fluid shear stress pathway activity through histone H3K79 homocysteinylation in hyperhomocysteinemia-related child hypertension.

BACKGROUND: The rise of hypertension in children has been increasingly associated with hyperhomocysteinemia (HHcy), which is recognized as a major risk factor. However, the underlying mechanisms linking homocysteine and hypertension (termed HHYP) are not fully understood. METHODS: This study utilized plasma samples from 27 control children and 27 children with HHYP (aged 8 ~ 16 years) for TMT6-labeled proteomic quantification, identifying significant altered proteins. Bioinformatics analysis revealed pathway alterations. Verification was carried out via parallel reaction monitoring (PRM) and western blot (WB) analyses. Additionally, a rat model of HHYP induced by high methionine diets, and umbilical vein endothelial cell models exposed to high homocysteine (hcy) levels were developed to investigate the molecular underpinnings further. Protein expression changes and epigenetic modifications were assessed using WB, immunohistochemistry (IHC), and ChIP-qPCR techniques. RESULTS: Key findings indicated that 357 proteins and 69 pathways were altered in children with HHYP. Specifically, 12 proteins within the fluid shear stress and atherosclerosis (FSSA) pathway showed differential expression, including the downregulation of TRX1 and GPX1 and the upregulation of ICAM1. The same expression patterns were noted in both the HHYP rat aortic tissues and the high hcy cultured endothelial cells. Moreover, elevated H3K79hcy modification levels were observed alongside epigenetic regulation of genes related to the FSSA pathway. Importantly, folic acid (FA), a medication frequently used in the clinical treatment of HHYP, has been demonstrated to effectively reverse H3K79hcy modifications and restore the disrupted FSSA pathway in both animal models and cell cultures. CONCLUSIONS: The present study suggests that HHcy may contribute to hypertension through the epigenetic dysregulation of the FSSA pathway mediated by H3K79hcy. Furthermore, the pediatric proteomics data gleaned from this study offer new clinical insights into the pathophysiology of HHYP in children.

Hyperhomocysteinemia↗
PubMed2002

Epigenetic history of an Arabidopsis trans-silencer locus and a test for relay of trans-silencing activity.

BACKGROUND: Meiotically heritable epimutations affecting transgene expression are not well understood, even and in particular in the plant model species, Arabidopsis thaliana. The Arabidopsis trans-silencer locus, C73, which encodes a fusion protein between the repressor of photomorphogenesis, COP1, and green fluorescent protein (GFP-COP1), heritably modifies the expression pattern and cop1-like cosuppression phenotypes of multiple GFP-COP1 target loci by transcriptional gene silencing. RESULTS: Here we describe three additional features of trans-silencing by the C73 locus. First, the silencing phenotype of C73 and of similar complex loci was acquired epigenetically over the course of no more than two plant generations via a stage resembling posttranscriptional silencing. Second, imprints imposed by the C73 locus were maintained heritably for at least five generations in the absence of the silencer with only sporadic spontaneous reversion. Third, the pairing of two other GFP-COP1 transgene loci, L91 and E82, showed an increased tendency for epigenetic modification when L91 carried an epigenetic imprint from C73, but not when E82 bore the imprint. CONCLUSIONS: The latter data suggest a transfer of trans-silencing activity from one transgene locus, C73, to another, namely L91. These results extend our operational understanding of interactions among transgenes in Arabidopsis.

Arabidopsis↗
PubMed2006

Counting divisions in a human somatic cell tree: how, what and why?

The billions of cells within an individual can be organized by genealogy into a single somatic cell tree that starts from the zygote and ends with present day cells. In theory, this tree can be reconstructed from replication errors that surreptitiously record divisions and ancestry. Such a molecular clock approach is currently impractical because somatic mutations are rare, but more feasible measurements are possible by substituting instead the 5' to 3' order of epigenetic modifications such as CpG methylation. Epigenetic somatic errors are readily detected as age-related changes in methylation, which suggests certain adult stem cells divide frequently and "compete" for survival within niches. Potentially the genealogy of any human cell may be reconstructed without prior experimental manipulation by merely reading histories recorded in their genomes.

Biological Clocks↗
PubMed2025

Multiomics Reveal Associations Between CpG Methylation, Histone Modifications and Transcription in a Species That has Lost DNMT3, the Colorado Potato Beetle.

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.

Animals↗
PubMed1998

Influence of epigenetic changes during oocyte growth on nuclear reprogramming after nuclear transfer.

Genomic imprinting is the epigenetic mechanism that distinguishes whether the loci that are inherited from the maternal or paternal genome lead to parent-specific gene expression. The mechanism also regulates development in mammalian embryos. Genomic imprinting is established after implantation according to the specific markers that are imposed on the genome during gametogenesis; the allele-specific gene expression is then maintained throughout embryogenesis. The genomic imprinting markers are erased and renewed on an own-sex basis only in cells that differentiate into germline cells. This report shows that the epigenetic modifications that occur during oogenesis perform the crucial function of establishing the allele-specific expression of imprinted genes, and also suggests that the epigenetic DNA modification is related to the reprogramming and aberrant development seen in manipulated embryos.

Animals↗
PubMed2005

Diagnostic and therapeutic applications of epigenetics.

Epigenetic abnormalities, such as aberrant methylation of CpG islands, are inherited over cell divisions, and play important roles in carcinogenesis. Aberrant methylation of CpG islands specific to tumor cells can be used as a marker to detect cancer cells or cancer-derived DNA, taking advantage of the high sensitivity of methods to detect aberrant methylation. Methylations of specific genes or methylation patterns of groups of genes were found to be associated with responses to chemotherapeutics and prognosis. Methylation in non-cancerous tissues is now attracting attention as a tumor risk marker, and is emerging as a target for cancer prevention. Epigenetic alterations are potentially reversible. The use of DNA demethylating agents has turned out to be effective for hematological malignancies, and is being tested in solid tumors. Histone deacetylase inhibitors and methods for gene-specific epigenetic modification are being developed. Application of epigenetics to cancer diagnostics and therapeutics, and possibly to cancer prevention, is coming into clinics.

Biomarkers, Tumor↗
PubMed2003

Oncogenomics: prospects for the future.

Genomics has generated a wealth of data that is now being used to identify additional molecular alterations associated with cancer development. Mapping these alterations in the cancer genome is a critical first step in dissecting oncological pathways. There are two ways in which cancer research has changed in recent years. The first is the progressive elucidation of the genomic basis of cancer. This has been accomplished by the generation of detailed information using procedures such as global expression profiling. The second is a renewed emphasis on the role of epigenetic modifications in the etiology of cancer. Changes in DNA methylation and chromatin modification patterns are some of the epigenetic factors that cause gene deregulation in cancer. In this article, current and evolving genomic applications and the hypotheses underlying the modality for cancer therapy will be reviewed.

Animals↗
PubMed2007

Epigenetic modulation of endogenous tumor suppressor expression in lung cancer xenografts suppresses tumorigenicity.

Epigenetic changes involved in cancer development, unlike genetic changes, are reversible. DNA methyltransferase and histone deacetylase inhibitors show antiproliferative effects in vitro, through tumor suppressor reactivation and induction of apoptosis. Such inhibitors have shown activity in the treatment of hematologic disorders but there is little data concerning their effectiveness in treatment of solid tumors. FHIT, WWOX and other tumor suppressor genes are frequently epigenetically inactivated in lung cancers. Lung cancer cell clones carrying conditional FHIT or WWOX transgenes showed significant suppression of xenograft tumor growth after induction of expression of the FHIT or WWOX transgene, suggesting that treatments to restore endogenous Fhit and Wwox expression in lung cancers would result in decreased tumorigenicity. H1299 lung cancer cells, lacking Fhit, Wwox, p16(INK4a) and Rassf1a expression due to epigenetic modifications, were used to assess efficacy of epigenetically targeted protocols in suppressing growth of lung tumors, by injection of 5-aza-2-deoxycytidine (AZA) and trichostatin A (TSA) in nude mice with established H1299 tumors. High doses of intraperitoneal AZA/TSA suppressed growth of small tumors but did not affect large tumors (200 mm(3)); lower AZA doses, administered intraperitoneally or intratumorally, suppressed growth of small tumors without apparent toxicity. Responding tumors showed restoration of Fhit, Wwox, p16(INKa), Rassf1a expression, low mitotic activity, high apoptotic fraction and activation of caspase 3. These preclinical studies show the therapeutic potential of restoration of tumor suppressor expression through epigenetic modulation and the promise of re-expressed tumor suppressors as markers and effectors of the responses.

Acid Anhydride Hydrolases↗
PubMed2004

Epigenetic reprogramming during early development in mammals.

Epigenetic modifications serve as an extension of the information content by which the underlying genetic code may be interpreted. These modifications mark genomic regions and act as heritable and stable instructions for the specification of chromatin organisation and structure that dictate transcriptional states. In mammals, DNA methylation and the modification of histones account for the major epigenetic alterations. Two cycles of DNA methylation reprogramming have been characterised. During germ cell development, epigenetic reprogramming of DNA methylation resets parent-of-origin based genomic imprints and restores totipotency to gametes. On fertilisation, the second cycle is triggered resulting in an asymmetric difference between parental genomes. Further epigenetic asymmetry is evident in the establishment of the first two lineages at the blastocyst stage. This differentiative event sets the epigenetic characteristics of the lineages as derivatives of the inner cell mass (somatic) and trophectoderm (extra-embryonic). It is the erasure and subsequent re-tracing of the epigenetic checkpoints that pose the most serious obstacles to somatic nuclear transfer. Elaboration of the mechanisms of these interactions will be invaluable in our fundamental understanding of biological processes and in achieving substantial therapeutic advances.

Animals↗
PubMed2005

Differences in the pattern of X-linked gene expression between fetal bovine muscle and fibroblast cultures derived from the same muscle biopsies.

The sex determination system in mammals creates an imbalance between males and females in the number of X chromosomes. This imbalance is compensated through transcriptional silencing of one of the two X chromosomes in female diploid cells by epigenetic modifications. Although common for mammals, X inactivation shows marked species-specific differences in mechanisms and end results, and provides a unique opportunity to study epigenetic regulation of gene expression. The aim of the present study was to establish the expression pattern of selected X-linked genes in bovine fetal muscle tissue and muscle fibroblast cultures in order to follow possible modifications at the transcriptional level attributable to in vitro culture. We used heterologous cDNA microarray hybridization and quantitative real-time PCR to study the pattern of expression of X-linked genes including SLC25A6, GAB3, MECP2, RPS4X, JARID1C, UBE1, BIRC4 and SLC16A2. Quantitative real-time PCR analysis in fetal bovine muscle showed higher transcript levels in females for all X-linked genes tested with the exception of SLC25A6, with differences being significant for RPS4X, JARID1C and UBE1. The expression in fibroblast cultures derived from the same samples differed, with significantly higher levels for UBE1, GAB3 and BIRC4, while the rest of the panel of X-linked genes remained unchanged. The changed expression pattern in vitro, probably reflecting modifications in the epigenetic mechanisms that regulate transcriptional activity and gene silencing in X inactivation, has important implications for the advancement of new biotechnologies such as somatic cell nuclear transfer and stem cell therapy.

Animals↗
PubMed1996

DNA methylation patterns in human tissues of uniparental origin using a zinc-finger gene (ZNF127) from the Angelman/Prader-Willi region.

In order to further our understanding of the epigenetic modifications of DNA and its role in imprinting, we examined DNA methylation patterns of human tissues of uniparental origin. We used complete hydatidiform moles (CHM), which are totally androgenetic conceptions, to examine the paternal methylation pattern in the absence of a maternal contribution and we used ovarian teratomas to represent the maternal counterpart. We carried out an analysis of DNA methylation of a gene which has been shown to contain sites which are differentially methylated in a parent-specific fashion. The gene, ZNF127, is located on chromosome 15q11-q13 in the region associated with Prader-Willi and Angelman syndromes. The parent-of-origin DNA methylation has been postulated to reflect the presence of an imprint and recent studies have confirmed that ZNF127 is differentially expressed only from the paternal chromosome. We identified a unique pattern of hyper- and hypomethylated sites in androgenetic conceptions which was nearly identical to the paternal pattern found in sperm. This may represent the paternal germ-line methylation imprint. We also studied partial hydatidiform moles, non-molar triploid conceptions, normal chorionic villi, and somatic tissue. These all demonstrated a modified DNA methylation pattern characteristic of normal chorionic villi with only limited findings of the imprint. Our results suggest that human androgenetic conceptions may provide an excellent model to analyze epigenetic DNA modifications, such as methylation, in imprinted genes. The paternal allele-specific methylation imprint will also be useful clinically to confirm the androgenetic nature of suspected molar conceptions in which parental blood samples may not be available.

Angelman Syndrome↗
PubMed2026

Beyond oncogenesis: The emerging role of EZH2 in tumor microenvironment.

Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and the catalytic component of Polycomb Repressive Complex 2, facilitates epigenetic modifications via the repressive H3K27me3 mark, consequently modulating the expression of numerous genes implicated in cellular proliferation and survival. Overexpression or dysregulation of EZH2 has been observed extensively across several malignancies, where it plays a major role in shaping the tumor microenvironment, promoting angiogenesis, cytokine secretion, and matrix remodeling. EZH2 mediates immune evasion, particularly in response to immunotherapy and checkpoint blockade. These interactions also position EZH2 as a key mediator of therapy resistance to chemotherapy, immunotherapy, and targeted therapy. Consequently, a comprehensive understanding of EZH2's function and its interactions within the TME and during cancer progression is crucial. This review aims to enhance the current understanding of EZH2 and its roles in the TME, cancer development, and therapeutic responses. This review will discuss the canonical and non-canonical functions of EZH2, summarize its established and evolving roles in cancer and the TME, and highlight its effects on tumor immunity and therapeutic efficacy.

Humans↗
PubMed1999

Expression and sequence requirements for nitrite reductase co-suppression.

We have previously reported that the introduction of a full-length tobacco nitrite reductase Nii1 cDNA under the control of the 35S promoter triggers co-suppression of endogenous Nii genes in 25% of tobacco transformants. Here we show that introduction of chimeric Nii1-uidA, uidA-Nii1 and Nii1-uidA-Nii1 transgenes carrying 186 bp of the 5' end and/or 241 bp of the 3' end of the Nii1 cDNA do not trigger co-suppression of endogenous Nii genes. In addition, we show that when introduced by crossing or transformation into co-suppressed transgenic tobacco lines carrying full-length Nii1 transgenes, these chimeric transgenes are not silenced. These results therefore suggest that the 5' and 3' ends of the Nii1 cDNA are not sufficient to trigger co-suppression and are not targets for homology-dependent RNA degradation. Surprisingly, co-suppression was released in a double transformant obtained by introduction of one of these constructs into the co-suppressed transgenic tobacco line 461-2.1 homozygous for a full-length Nii1 transgene, and in one plant regenerated from untransformed leaf discs (plant 461-2.1*). The reappearance of co-suppression at very low frequency (less than 10(-3)) in the F2 progeny of plant 461-2.1* and the apparent absence of structural modification of the transgene locus suggest a metastable epigenetic modification. The steady-state level of Nii mRNAs in the plant 461-2-.1* was higher than in wild-type plants but lower than in hemizygous plants 461-2.1 which never trigger silencing. These results therefore confirm that transcription of the transgene above a particular threshold is required to trigger co-suppression.

DNA Methylation↗
PubMed1991

Effect of egg composition on the developmental capacity of androgenetic mouse embryos.

Analysis of the developmental capacities of androgenetic and gynogenetic mouse embryos (bearing two paternal or two maternal pronuclei, respectively) revealed a defect in blastocyst formation of androgenetic, but not gynogenetic, embryos that was a function of the maternal genotype. Androgenetic embryos constructed using fertilized eggs from C57BL/6 or (B6D2)F1 mice developed to the blastocyst stage at frequencies similar to those previously reported, whereas androgenetic embryos constructed with fertilized eggs from DBA/2 mice developed poorly, the majority failing to progress beyond the 16-cell stage and unable to form a blastocoel-like cavity, regardless of whether the male pronuclei were of C57BL6 or DBA/2 origin. This impaired development was observed even in androgenetic embryos constructed by transplanting two male pronuclei from fertilized DBA/2 eggs to enucleated C57BL/6 eggs, indicating that the defect cannot be explained as the lack of some essential component in the DBA/2 cytoplasm that might otherwise compensate for androgeny. Rather, the DBA/2 egg cytoplasm apparently modifies the incoming male pronuclei differently than does C57BL/6 egg cytoplasm. Several specific alterations in the protein synthesis pattern of DBA/2 androgenones were observed that reflect a defect in the regulatory mechanisms that normally modulate the synthesis of these proteins between the 8-cell and blastocyst stages. These results are consistent with a model in which cytoplasmic factors present in the egg direct a strain-dependent modification of paternal genome function in response to epigenetic modifications (genomic imprinting) established during gametogenesis and indicate that preimplantation development can be affected by these modifications at both the morphological and biochemical levels.

Animals↗
PubMed2004

The indexing potential of histone lysine methylation.

Diverse post-translational modifications of histone N-termini represent an important epigenetic mechanism for the organization of chromatin structure and the regulation of gene activity. Within the last three years, great progress has been made in understanding the functional implications of histone methylation, in particular through the characterization of histone methyltransferases (HMTases) that direct the site-specific methylation of lysine positions in the histone H3 N-terminus. Histone lysine methylation has been linked with pericentric heterochromatin formation, X-inactivation, Polycomb group (Pc-G)-dependent gene repression and epigenetic control of transcription units at euchromatic positions. Together, these regulatory roles have strongly established histone lysine methylation as a central epigenetic modification for the organization of eukaryotic chromatin. However, they also create a paradox: if histone lysine methylation is present at so many chromatin regions, how can it impart epigenetic information? We provide evidence that differences in distinct methylation states (mono- vs. di- vs. trimethylation) and selective combinations of individually methylated lysine positions can indeed index chromatin regions, resulting in epigenetic landmarks for the partitioning of eukaryotic chromatin.

Animals↗
PubMed2006

Quantitative assessment of DNA methylation: Potential applications for disease diagnosis, classification, and prognosis in clinical settings.

Deregulation of the epigenome is now recognized as a major mechanism involved in the development and progression of human diseases such as cancer. As opposed to the irreversible nature of genetic events, which introduce changes in the primary DNA sequence, epigenetic modifications are reversible and leave the original DNA sequence intact. There is now evidence that the epigenetic landscape in humans undergoes modifications as the result of normal aging, with older individuals exhibiting higher levels of promoter hypermethylation compared to younger ones. Thus, it has been proposed that the higher incidence of certain disease in older individuals might be, in part, a consequence of an inherent change in the control and regulation of the epigenome. These observations are of remarkable clinical significance since the aberrant epigenetic changes characteristic of disease provide a unique platform for the development of new therapeutic approaches. In this review, we address the significance of DNA methylation changes that result or lead to disease, occur with aging, or may be the result of environmental exposure. We provide a detailed description of quantitative techniques currently available for the detection and analysis of DNA methylation and provide a comprehensive framework that may allow for the incorporation of protocols which include DNA methylation as a tool for disease diagnosis and classification, which could lead to the tailoring of therapeutic approaches designed to individual patient needs.

Chromatography, High Pressure Liquid↗
PubMed2003

Natural selection and the evolution of genome imprinting.

Sexual reproduction results from the fusion of gametes in which the chromatin configuration of maternal and paternal chromosomes is distinct at fertilization. Although many of the differences are erased during successive cellular divisions and chromatin modifications, some are retained in both somatic and germline cells. These epigenetic modifications can confer different characteristics on maternal and paternal chromosomes and such differences can be selected during any process that has the ability to distinguish between homologues. The end result of these selective forces are parental origin effects, writ large. The range of effects observed, including transcriptional imprinting and effects on chromosome segregation and heterochromatization, reflects the diversity of selective forces in operation. However, a closer look at these effects suggests that parental origin-dependent differences in chromatin structure might be subject to some common forces and that these forces may explain many of the "nontranscriptional" parental origin effects observed in mammals.

Animals↗
PubMed2006

Fetal origins of breast cancer.

Susceptibility to breast cancer might be pre-determined in utero. Alterations in the fetal hormonal environment, caused by either maternal diet or exposure to environmental factors with endocrine activities, can modify the epigenome, and these modifications are inherited in somatic daughter cells and maintained throughout life. These epigenetic modifications might lead to changes in mammary gland development, such as increased vulnerability of epithelial targets for malignant transformation. According to this hypothesis, on post-pubertal exposure to an initiating factor, such as a carcinogen, high levels of hormones and radiation, the mammary epithelial targets, perhaps stem cells, in terminal end buds/terminal ductal lobular units would be at an increased risk of malignant transformation. The increased susceptibility for cancer initiation might result from high levels of cell proliferation, reduced apoptosis and/or altered stromal regulation. Thus, maternal diet and environmental exposure might increase the risk of breast cancer by inducing permanent epigenetic changes in the fetus that alter the susceptibility to factors that can initiate breast cancer. Identifying the epigenetically altered target genes and their ligands might lead to strategies to prevent this disease in some women.

Animals↗