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Results for “epigenetic modification”

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At least 217 records · Page 12Linked to original sources
PubMed2005

Delving into the diversity of facultative heterochromatin: the epigenetics of the inactive X chromosome.

X chromosome inactivation represents one of the most dramatic examples of mono-allelic gene expression and long-term gene-silencing in mammals. The key regulatory molecule that triggers silencing is the Xist transcript, but little is known about its repressive action. Some progress has been made in deciphering the epigenetics of the inactive state that it triggers, however. During pre-implantation development, the inactive state is relatively labile. Later on, in the soma, the inactive state is highly stable and clonally heritable. This is ensured by the panoply of epigenetic modifications that characterize the inactive X and, presumably, is also a result of its spatio-temporal segregation. The inactive X chromosome has been associated with an increasing number of histone modifications, and several recent studies have implicated Polycomb group proteins in laying down some of these marks. Thanks to genetic and biochemical approaches to analyse these proteins, the epigenetic tapestry of the inactive X is just beginning to be unravelled. Lineage-specific differences provide a glimpse into the developmental complexity of the epigenetic marks that ensure the inactive state.

Animals↗
PubMed2026

Inheritance of the epigenetic signature and reduced intermuscular bone phenotype acquired via DNA methylation editing of the runx2 b promoter in zebrafish.

The presence of intermuscular bones (IBs) can directly affect the economic value of aquaculture fish. Although genome editing can create IB-free fish by knocking out key IB-related genes, such as runx2b, the associated DNA sequence alterations raise food safety and health concerns, limiting its breeding applications. In this study, we used CRISPR/dCas9-mediated epigenome-editing technology targeting the runx2 b promoter in zebrafish to alter DNA methylation patterns without changing the DNA sequence. Our results showed that higher runx2 b promoter methylation patterns significantly inhibited eGFP mRNA expression levels in the recombinant plasmid. Using the CRISPR/dCas9-Dnmt7 system to enhance methylation of the zebrafish runx2b promoter, we observed a significant decrease in runx2 b mRNA expression levels in the F0 generation. The IBs in the 11 th-16 th muscle segments of the adult F0 fish were significantly shorter compared with the controls. Inbreeding of fish was used to produce F1 and F2 offspring that retained these high promoter methylation levels, along with persistent runx2b expression suppression and IB development inhibition. Transcriptome sequencing analysis suggested that increasing runx2 b promoter methylation levels may synergistically induce additional epigenetic modifications, potentially affecting the PPAR signaling pathway and FoxO transcription factor regulation, which appears to inhibit osteoblast proliferation and differentiation. Overall, this study demonstrates an innovative application of epigenetic editing technology for aquaculture breeding. By precisely regulating the expression patterns of key genes for economically important traits while preserving genomic DNA integrity, this approach provides a theoretical foundation and technical support for improving fish economic traits.

Animals↗
PubMed2025

Histone modifications in the regulation of erythropoiesis.

INTRODUCTION: The pathogenesis of anemia and other erythroid dysphasia are mains poorly understood, primarily due to limited knowledge about the differentiation processes and regulatory mechanisms governing erythropoiesis. Erythropoiesis is a highly complex and precise biological process, that can be categorized into three distinct stages: early erythropoiesis, terminal erythroid differentiation, and reticulocyte maturation, and this complex process is tightly controlled by multiple regulatory factors. Emerging evidence highlights the crucial role of epigenetic modifications, particularly histone modifications, in regulating erythropoiesis. Methylation and acetylation are two common modification forms that affect genome accessibility by altering the state of chromatin, thereby regulating gene expression during erythropoiesis. DISCUSSION: This review systematically examines the roles of histone methylation and acetylation, along with their respective regulatory enzymes, in regulating the development and differentiation of hematopoietic stem/progenitor cells (HSPCs) and erythroid progenitors. Furthermore, we discuss the involvement of these histone modifications in erythroid-specific developmental processes, including hemoglobin switching, chromatin condensation, and enucleation.Conclusions This review summarizes the current understanding of the role of histone modifications in erythropoiesis based on existing research, as a foundation for further research the mechanisms of epigenetic regulatory in erythropoiesis.

Erythropoiesis↗
PubMed2019

Histone H3 lysine K4 methylation and its role in learning and memory.

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.

Animals↗
PubMed2006

Developmental changes in DNA methylation and covalent histone modifications of chromatin associated with the epsilon-, gamma-, and beta-globin gene promoters in Papio anubis.

The baboon is a suitable and relevant animal model to study the mechanism of human globin gene switching. This investigation addresses the role of DNA methylation and histone coding in globin gene switching in the baboon, Papio anubis. Bisulfite sequencing and chromatin immunoprecipitation studies were performed in erythroid cells purified from fetuses of varying gestational ages and from adult bone marrow to analyze the manner that changes in DNA methylation of the epsilon-, gamma-, and beta-globin promoters and association of ac-H3, ac-H4, H3-dimeK4, H3-dimeK36, and H3-dimeK79 with the epsilon-, gamma-, and beta-globin promoters occur during development. Changes in DNA methylation of the epsilon- and gamma-globin gene promoters during transitional stages of globin gene switching were consistent with the stochastic model of methylation and a role of DNA methylation in gene silencing. Enrichment of ac-H3, ac-H4, and pol II at the promoters of developmentally active genes was observed, while the pattern of distribution of H3-dimeK4 and H3-dimeK79 suggests that these modifications are found near both currently and formerly active promoters. Enrichment of H3-dimeK36 at the silenced epsilon-globin gene promoter was observed. These studies demonstrate that coordinated epigenetic modifications in the chromatin structure of the beta-like globin gene promoters accompany the highly regulated changes in expression patterns of these genes during development.

Animals↗
PubMed2005

The essential role of histone H3 Lys9 di-methylation and MeCP2 binding in MGMT silencing with poor DNA methylation of the promoter CpG island.

Silencing of the O (6)-methylguanine-DNA methyltransferase (MGMT) gene, a key to DNA repair, is involved in carcinogenesis. Recent studies have focused on DNA hypermethylation of the promoter CpG island. However, cases showing silencing with DNA hypomethylation certainly exist, and the mechanism involved is not elucidated. To clarify this mechanism, we examined the dynamics of DNA methylation, histone acetylation, histone methylation, and binding of methyl-CpG binding proteins at the MGMT promoter region using four MGMT negative cell lines with various extents of DNA methylation. Histone H3K9 di-methylation (H3me2K9), not tri-methylation, and MeCP2 binding were commonly seen in all MGMT negative cell lines regardless of DNA methylation status. 5Aza-dC, but not TSA, restored gene expression, accompanied by a decrease in H3me2K9 and MeCP2 binding. In SaOS2 cells with the most hypomethylated CpG island, 5Aza-dC decreased H3me2K9 and MeCP2 binding with no effect on DNA methylation or histone acetylation. H3me2K9 and DNA methylation were restricted to in and around the island, indicating that epigenetic modification at the promoter CpG island is critical. We conclude that H3me2K9 and MeCP2 binding are common and more essential for MGMT silencing than DNA hypermethylation or histone deacetylation. The epigenetic mechanism leading to silent heterochromatin at the promoter CpG island may be the same in different types of cancer irrespective of the extent of DNA methylation.

Azacitidine↗
PubMed2005

Epigenetic up-regulation of C-C chemokine receptor 7 and C-X-C chemokine receptor 4 expression in melanoma cells.

Histone deacetylation and DNA methylation establish epigenetic modifications, which through chromatin remodeling may result in gene silencing. We hypothesized that chemokine receptors C-C chemokine receptor 7 (CCR7) and C-X-C chemokine receptor 4 (CXCR4) on melanoma cells undergo epigenetic regulation. We investigated whether a histone deacetylase inhibitor and a demethylating agent influence CCR7 and CXCR4 expression on melanoma cells. Initially, microarray analysis was done to screen changes in chemokine receptor expression on melanoma cells after treatment with trichostatin A (TSA) and 5-Aza-2-deoxycytidine (5-Aza). CCR7 and CXCR4 mRNA expression were uniformly altered and selected for further investigation. Quantitative real-time reverse transcription-PCR assay, immunohistochemistry, and Western blot analysis were used to assess changes in mRNA and protein expression induced by TSA and 5-Aza in melanoma lines. Cell migration assays were conducted to assess the effects of altered CCR7 and CXCR4 expression on cell function. Treatment with TSA or 5-Aza increased gene expression of both CCR7 and CXCR4 in melanoma lines. TSA was the strongest enhancer. With combined treatment, CCR7 and CXCR4 mRNA expression was also up-regulated. Immunohistochemistry after combined treatment showed enhanced staining of both CCR7 and CXCR4 compared with control cells. Melanoma cell migration in TSA- and 5-Aza-treated cells was 7- and 2-fold higher than control cells for CCR7 and CXCR4, respectively. In summary, a histone deacetylase inhibitor and a demethylating agent up-regulated CCR7 and CXCR4 expression on melanoma cells. This increase in chemokine receptor expression correlated with functional activity. Most importantly, we have identified an epigenetic mechanism that may endogenously regulate chemokine receptor expression on melanoma cells.

Acetylation↗
PubMed2026

A cooperative regulatory module between TAGL2 and JMJC1 activates specific defense genes against root-knot nematodes in tomato.

Plant-parasitic nematodes (PPNs) threaten global food security. Although epigenetic modifications are crucial for plant immunity, how histone modifiers contribute to root-knot nematodes (RKNs, Meloidogyne incognita) resistance remains unclear. Here, using genetic, molecular and biochemical approaches, we investigated the epigenetic and transcriptional mechanisms underlying RKN resistance mediated by the histone demethylase (HDM) JMJC1 and the MADS-box transcription factor TAGL2 in tomato (Solanum lycopersicum). We identified JMJC1 as an RKN-induced positive defense regulator targeting H3K9me3 and H3K27me3 histone marks. JMJC1 physically interacts with TAGL2, which also positively regulates RKN resistance. Transcriptomic analysis indicated that TAGL2 regulates multiple layers of the plant defense network, transcriptionally activating representative genes from distinct pathways (including PUB10, bHLH98, CCaMK, and SAUR3), which we validated as positive regulators of RKN resistance via virus-induced gene silencing (VIGS). At the chromatin level, TAGL2 and JMJC1 co-regulate these loci, associating with localized H3K9me3 and H3K27me3 reduction. Furthermore, TAGL2 directly activates JMJC1 transcription, establishing a positive feedback loop that amplifies immune signaling. Our findings reveal a cooperative model wherein a HDM and a transcription factor coordinate at specific loci to fine-tune multiple defense layers at both epigenetic and transcriptional levels, providing insights for breeding durable nematode-resistant plants.

Solanum lycopersicum↗
PubMed2002

Epi-alleles in plants: inheritance of epigenetic information over generations.

Epigenetic modification of plant gene and transposon activity, which correlates with their methylation, is often heritable over many generations. Such heritable properties allow conventional genetic linkage analysis to identify the sequences affected in epigenetic variants. Machinery controlling the establishment of the epigenetic state and role of the epigenetic controls in plant development are also discussed.

Alleles↗
PubMed2005

Targeting epigenetic changes in acute myeloid leukemia.

Recent advances in the understanding of acute myeloid leukemia (AML) and myeloid leukemogenesis have begun to narrow the focus of therapy to specific molecular aberrations that characterize subsets of this disease. Rather than embracing "one-fits-all" cytarabine-based chemotherapy as a standard approach for all patients, ongoing clinical research in AML focuses on drugs that target unique genomic aberrations, protein structure/functional alterations, or dysregulated cellular pathways that are specific for molecular subgroups of patients. Epigenetic modifications causing gene transcriptional repression have been associated with malignant transformation and are intriguing new targets in the treatment of AML. In contrast to genetic deletions causing irreversible loss of gene function, epigenetic gene silencing mediated by DNA methylation and histone deacetylation can be reversed via pharmacologic inhibition of DNA methyltransferases and histone deacetylases, respectively. When this occurs, normal patterns of gene expression, hematopoietic differentiation, and apoptosis may be restored and disease response obtained. In this review, we focus on the clinical applicability of epigenetic targeting in the treatment of patients with AML.

Acetylation↗
PubMedDate not supplied

Activation of the human GH gene cluster: roles for targeted chromatin modification.

The cluster of genes encoding the human growth hormone (GH) contains an array of five highly related genes. From 5' to 3' these are: GHN, CSL (encoding chorionic somatomammotropin-like gene), CSA, GHV (encoding GH-variant gene) and CSB. These five genes are expressed in mutually exclusive tissue distributions, GHN in pituitary somatotropes and the remaining four genes in placental villous syncytiotrophoblasts. The onset of GH expression during development is dependent upon epigenetic modifications at the GH locus under the control of its distal locus control region (LCR). A clear understanding of these normal epigenetic controls on the expression of GH could lead to new insights into the development and treatment of isolated GH deficiency in children. This review focuses on the role of the LCR in histone hyperacetylation at the GH locus and subsequent effects on the tissue-specific activation of these genes.

Acetyltransferases↗
PubMed2006

Epigenetics and phenotypic variation in mammals.

What causes phenotypic variation? By now it is clear that phenotype is a result of the interaction between genotype and environment, in addition to variation not readily attributable to either. Epigenetic phenomena associated with phenotypic variation at the biochemical, cellular, tissue, and organism level are now well recognized and are likely to contribute to the "intangible variation" alluded to. While it is clear that epigenetic modifications are mitotically heritable, the fidelity of this process is not well understood. Inheritance through more than one generation of meioses is even less well studied. So it remains unclear to what extent epigenetic changes contribute to phenotypic variation in natural populations. How might such evidence be obtained? What are the features of phenotypes that might suggest an epigenetic component? How much of the epigenetic component is truly independent of genetic changes? The answers to such questions must come from studies designed specifically to detect subtle, stochastically determined phenotypic variation in suitable animal models.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Epigenetic alchemy for cell fate conversion.

Recent progress in neural stem cell research shows that a number of extrinsic factors and intracellular mechanisms, including epigenetic modifications, are involved in the self-renewal of neural stem cells and in neuronal and glial differentiation. Remarkably, there is increasing evidence that the remodeling of chromatin structure and the alteration of epigenetic marks, including histone methylation and acetylation and DNA methylation, can cause committed cells to convert from one fate to another, and such converted cells are functional when transplanted in vivo. Thus, epigenetic research might generate the alchemy required to convert any non-neural stem cells into functional neural stem cells, which are few and difficult to extract from the adult central nervous system.

Animals↗
PubMed2006

[Genomic imprinting in the epigenetics of mammals].

Genomic imprinting is one of the most remarkable and important epigenetic phenomena. A biological ban on parthenogenetic and androgenetic development of mammals is an obvious consequence of genomic imprinting. Genomic imprinting defects may cause malformations, clinical syndromes, and tumor growth in humans and to the large offspring syndrome and an increased mortality after in vitro manipulations with early embryos in mammals. Differential expression of parental alleles during ontogeny implies a mechanism of reversible, selective marking of gene alleles. These relatively stable epigenetic modifications, which do not affect the primary nucleotide sequence of DNA, may be transmitted in somatic cell lines and reproduced in the germ line. The genomic imprinting mechanism may be involved in other epigenetic processes, such as epigenetic inheritance, nonrandom allele segregation, meiotic drive, etc. Artificial modulation of genomic imprinting effects with the use of growth factors and demethylating agents permits partial "normocoping" during the development of parthenogenetic mouse embryos. Targeted changes in the transcriptional activity of imprinted genes provide prerequisites for epigenetic correction of syndromes and diseases caused by genomic imprinting defects.

Animals↗
PubMed2003

Epigenetic transitions: towards therapeutic targets.

Therapeutic approaches aimed at developing epigenetically-effective drugs are under intense investigation. Several classes of enzymes regulating histone acetylation and DNA methylation, which are required for epigenetic transitions, offer attractive targets for therapeutic interventions. Imbalances in histone acetylation and DNA methylation may play a significant role in the development of cancer and leukaemia and may provide a mechanistic rationale for targeting epigenetic modifications. Clinical trials designed to evaluate inhibitors of DNA methylation and histone deacetylase inhibitors are showing encouraging results in cancer patients. A growing quantity of data from preclinical research supports the notion that epigenetically-effective drugs could also find an application in other therapeutic areas. A number of emerging biomarkers may prove useful for monitoring drug effects and defining molecular signatures of response, toxicity and effective dose.

Acetylation↗
PubMed2003

Transgenic swine for biomedicine and agriculture.

Initial technologies for creating transgenic swine only permitted random integration of the construct. However, by combining the technology for homologous recombination in fetal somatic cells with that of nuclear transfer (NT), it is now possible to create specific modifications to the swine genome. The first such example is that of knocking out a gene that is responsible for hyperacute rejection (HAR) when organs from swine are transferred to primates. Because swine are widely used as models of human diseases, there are opportunities for genetic modification to alter these models or to create additional models of human disease. Unfortunately, some of the offspring resulting from NT have abnormal phenotypes. However, it appears that these abnormal phenotypes are a result of epigenetic modifications and, thus, are not transmitted to the offspring of the clones. Although the technique of producing animals with specific genetic modifications by NT has been achieved, improvements to the NT technique as well as improvements in the culture conditions for somatic cells and the techniques for genetic modification are still needed.

Agriculture↗
PubMed2004

MDR1, chemotherapy and chromatin remodeling.

The development of multidrug resistance (MDR) in cancer can severely impede the efficacy of chemotherapy treatment. P-glycoprotein (Pgp) overexpression, encoded by the MDR1 gene, is a well-established mediator of MDR. MDR1 expression is rapidly upregulated by chemotherapeutic drugs and a number of other exogenous stimuli, however the mechanisms underlying its transcriptional regulation remain unclear. In recent years, research has indicated that chromatin accessibility, or epigenetic modifications, will play a large role in controlling the endogenous MDR1 expression state, and its response to activation stimuli. This review examines some of these studies, and discusses how new developments from the greatly expanding epigenetics field may extend to MDR1 transcriptional research.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Disruption of the plant gene MOM releases transcriptional silencing of methylated genes.

Epigenetic modifications change transcription patterns in multicellular organisms to achieve tissue-specific gene expression and inactivate alien DNA such as transposons or transgenes. In plants and animals, DNA methylation is involved in heritability and flexibility of epigenetic states, although its function is far from clear. We have isolated an Arabidopsis gene, MOM, whose product is required for the maintenance of transcriptional gene silencing. Mutation of this gene or depletion of its transcript by expression of antisense RNA reactivates transcription from several previously silent, heavily methylated loci. Despite this, the dense methylation at these reactivated loci is maintained even after nine generations, indicating that transcriptional activity and methylation pattern are inherited independently. The predicted MOM gene product is a nuclear protein of 2,001 amino acids containing a region similar to part of the ATPase region of the SWI2/SNF2 family, members of which are involved in chromatin remodelling. MOM is the first known molecular component that is essential for transcriptional gene silencing and does not affect methylation pattern. Thus, it may act downstream of methylation in epigenetic regulation, or be part of a new pathway that does not require methylation marks.

ATPases Associated with Diverse Cellular Activitie↗