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Results for “epigenetic modification”

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At least 919 records · Page 51Linked to original sources
PubMed1998

Differential preimplantation regulation of two mouse homologues of the yeast SWI2 protein.

Epigenetic regulation of gene expression through modification of chromatin organization is an important mechanism in the development of eucaryotic organisms. We investigated the developmentally regulated expression of the mouse mBRG1 and mbrm genes, which are homologous to the yeast SWI2 gene. Both proteins are involved in chromatin remodeling as components of the mammalian SWI/SNF complex. The analysis was performed at a time in mouse development when the formation of a functional zygotic nucleus is closely linked to extensive chromatin modifications. Reverse transcription-polymerase chain reaction (RT-PCR) analysis in mature oocytes and through the first cleavage stages showed that both genes were highly expressed as maternal products but that they subsequently exhibited considerable differences in their level of expression when the transition to zygotic transcription occurred. Immunodetection of the two proteins with specific antibodies paralleled the RT-PCR analysis. The mBRG1 protein was present throughout preimplantation development, whereas zygotic mbrm was clearly detectable only when differentiation first occurs at the blastocyst stage. At this stage, mbrm was restricted to the inner cell mass. Cell type-specific expression of mbrm was also observed after in vitro differentiation of embryonic stem cells. These results indicate that the two murine homologues of SWI2 have substantially different roles in chromatin organization during the onset of embryonic development.

Animals↗
PubMed2005

The role of the RNAi machinery in heterochromatin formation.

Considerable effort has been devoted to the characterization of RNA interference (RNAi), a posttranscriptional gene silencing mechanism involving small RNA-containing effector complexes. Recent studies have revealed that components of the RNAi machinery are associated not only with target RNA cleavage and impairment of target RNA translation but also with the formation of heterochromatin. There is increasing evidence that RNA-mediated chromatin modifications play an important role in epigenetic transcriptional gene silencing.

Animals↗
PubMed2026

Genomic and epigenetic regulatory mechanisms in exercise-based rehabilitation processes: Cellular and tissue remodeling, microvascular adaptation, and circulating biomarkers.

While exercise-based rehabilitation is known to positively impact functionally related parameters, the role of genomic and epigenomic responses coordinated with cellular, extracellular matrix (ECM), mitochondrial, and microvascular adaptations remains insufficiently investigated. This narrative review summarizes mechanistic evidence linking exercise-associated mechanical, metabolic, hypoxia-redox, inflammatory, and hemodynamic stimuli with tissue remodeling and clinically relevant biomarkers. Current findings indicate that integrin-focal adhesion kinase (FAK) signaling and Hippo YAP/TAZ pathways contribute to mechanical signal transduction, cytoskeletal regulation, and gene expression, whereas metabolic adaptation, ATP homeostasis, and protein synthesis are regulated through AMPK-PGC-1α, SIRT1, and mTOR-dependent pathways. Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and noncoding RNA regulation, further influence cell-specific responses in myofibers, satellite cells, fibro-adipogenic progenitors, endothelial cells, pericytes, and immune cells. In addition, VEGF-VEGFR2, eNOS-NO, and KLF2/KLF4 signaling, together with extracellular matrix turnover and inflammation resolution, contribute to tissue repair and microvascular adaptation during rehabilitation. Importantly, acute exercise-induced molecular responses should not be interpreted as direct evidence of sustained tissue adaptation. Circulating microRNAs, extracellular vesicles, cell-free DNA, collagen-related markers, and vascular proteins represent promising approaches for monitoring rehabilitation-related changes; however, their clinical translation remains limited by challenges related to tissue specificity, biomarker kinetics, analytical variability, and the need for standardized validation alongside structural and functional outcomes.

AMPK–PGC-1α signaling↗
PubMed2004

Human cancer, PTEN and the PI-3 kinase pathway.

The PI-3 kinase pathway is a major driving force for human cancer. One common way of stimulating the PI-3 kinase pathway occurs through inactivation of the PTEN tumor suppressor. The mechanisms of PTEN inactivation include mutation, epigenetic silencing and post-translational modification. Improved insight into the regulation of PTEN is leading to a richer understanding of the contribution of PTEN and the PI-3 kinase pathway to human tumors. Understanding the pathology of PI-3 kinase signaling in tumors improves knowledge of cancer etiology and provides novel therapeutic targets.

Animals↗
PubMed2005

Epigenetic control of B cell differentiation.

Gene expression, differentiation and the specialized function of various cell types are controlled epigenetically by post-translational histone modifications. These modifications establish a "histone code" that is recognized by various regulatory proteins, thereby creating a stable pattern of gene expression. The focus of this review is to discuss how the chromatin modifications regulate immunoglobulin gene rearrangement and B cell differentiation.

Animals↗
PubMed2006

2. Chromatin assembly with H3 histones: full throttle down multiple pathways.

The typical eukaryotic genome packages roughly 6 feet of DNA into a nucleus about 5 mum in diameter, yet this compaction blocks access to the DNA. At the first level of compaction, DNA is wrapped around octamers of core histone proteins to form arrays of nucleosomes. Nucleosomes are sufficient to block access to DNA, and cells must therefore manipulate nucleosomes in the course of activating the genome. Dramatic progress has been made in understanding the mechanisms by which nucleosomes are manipulated. In addition to the major core histones, most eukaryotic genomes also encode additional variant histones, which have some structural similarity. These are targeted to specific loci by coupling specialized nucleosome assembly pathways to DNA replication, transcription, or to developmental processes. We review evidence that nucleosome assembly pathways are interlinked with histone-modification systems, and may thereby perpetuate epigenetic chromatin states.

Animals↗
PubMed2004

Imprinting on distal chromosome 7 in the placenta involves repressive histone methylation independent of DNA methylation.

Imprinted genes are expressed from only one of the parental chromosomes and are marked epigenetically by DNA methylation and histone modifications. The imprinting center 2 (IC2) on mouse distal chromosome 7 is flanked by several paternally repressed genes, with the more distant ones imprinted exclusively in the placenta. We found that most of these genes lack parent-specific DNA methylation, and genetic ablation of methylation does not lead to loss of their imprinting in the trophoblast (placenta). The silent paternal alleles of the genes are marked in the trophoblast by repressive histone modifications (dimethylation at Lys9 of histone H3 and trimethylation at Lys27 of histone H3), which are disrupted when IC2 is deleted, leading to reactivation of the paternal alleles. Thus, repressive histone methylation is recruited by IC2 (potentially through a noncoding antisense RNA) to the paternal chromosome in a region of at least 700 kb and maintains imprinting in this cluster in the placenta, independently of DNA methylation. We propose that an evolutionarily older imprinting mechanism limited to extraembryonic tissues was based on histone modifications, and that this mechanism was subsequently made more stable for use in embryonic lineages by the recruitment of DNA methylation.

Animals↗
PubMed2005

Unexpected roles for deacetylation in interferon- and cytokine-induced transcription.

Protein acetylation is a reversible modification that has been implicated in epigenetic regulation of gene expression. It is widely accepted that acetylation enzymes are present at transcriptionally active promoters and deacetylation enzymes associate with transcriptionally silent loci. These results notwithstanding, recent findings indicate that positive regulation of gene expression by interferons and other cytokines requires both acetylation and deacetylation.

Acetylation↗
PubMed2005

Role of histone acetylation in the control of gene expression.

Histone proteins play structural and functional roles in all nuclear processes. They undergo different types of covalent modifications, defined in their ensemble as epigenetic because changes in DNA sequences are not involved. Histone acetylation emerges as a central switch that allows interconversion between permissive and repressive chromatin domains in terms of transcriptional competence. The mechanisms underlying the histone acetylation-dependent control of gene expression include a direct effect on the stability of nucleosomal arrays and the creation of docking sites for the binding of regulatory proteins. Histone acetyltransferases and deacetylases are, respectively, the enzymes devoted to the addition and removal of acetyl groups from lysine residues on the histone N-terminal tails. The enzymes exert fundamental roles in developmental processes and their deregulation has been linked to the progression of diverse human disorders, including cancer.

Acetylation↗
PubMed2004

Differential dynamics of histone H3 methylation at positions K4 and K9 in the mouse zygote.

BACKGROUND: In the mouse zygote the paternal genome undergoes dramatic structural and epigenetic changes. Chromosomes are decondensed, protamines replaced by histones and DNA is rapidly and actively demethylated. The epigenetic asymmetry between parental genomes remains at least until the 2-cell stage suggesting functional differences between paternal and maternal genomes during early cleavage stages. RESULTS: Here we analyzed the timing of histone deposition on the paternal pronucleus and the dynamics of histone H3 methylation (H3/K4mono-, H3/K4tri- and H3/K9di-methylation) immediately after fertilization. Whereas maternal chromatin maintains all types of histone H3 methylation throughout the zygotic development, paternal chromosomes acquire new and unmodified histones shortly after fertilization. In the following hours we observe a gradual increase in H3/K4mono-methylation whereas H3/K4tri-methylation is not present before latest pronuclear stages. Histone H3/K9di-methylation is completely absent from the paternal pronucleus, including metaphase chromosomes of the first mitotic stage. CONCLUSION: Parallel to the epigenetic asymmetry in DNA methylation, chromatin modifications are also different between both parental genomes in the very first hours post fertilization. Whereas methylation at H3/K4 gradually becomes similar between both genomes, H3/K9 methylation remains asymmetric.

Animals↗
PubMed2026

Multi-omics approaches in idiopathic pulmonary fibrosis: from molecular mechanisms to therapeutic targets and precision medicine.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited therapeutic options and marked molecular heterogeneity. Despite available antifibrotic therapies, disease progression remains poorly predictable, highlighting the need for improved mechanistic understanding and therapeutic targeting. This review summarizes recent advances in multi-omics research to elucidate the molecular mechanisms underlying IPF and to identify potential biomarkers and pharmacological targets. Multi-omics studies, including genomics, epigenomics, transcriptomics, proteomics, metabolomics, microbiome profiling, and single-cell sequencing, have revealed key pathogenic mechanisms in IPF. Genetic susceptibility factors such as MUC5B promoter variants and telomere-related genes contribute to disease risk. Epigenetic regulation, including DNA methylation, histone modifications, and non-coding RNAs, plays a central role in fibrotic remodeling. Transcriptomic and proteomic analyses have identified dysregulated signaling pathways, including TGF-β, mTOR, cellular senescence, and extracellular matrix remodeling. Metabolomic alterations indicate disrupted lipid and amino acid metabolism. Importantly, integration of multi-omics datasets enables the identification of molecular endotypes, candidate biomarkers, and potential therapeutic targets. However, challenges including data integration, tissue heterogeneity, limited cohort size, and the need for functional validation remain important barriers to clinical translation. Continued development of multi-omics approaches may facilitate more accurate disease classification and support the development of personalized therapeutic strategies for IPF.

biomarkers↗
PubMed2006

Cross-species clues of an epigenetic imprinting regulatory code for the IGF2R gene.

The epigenetic marks on the IGF2R gene that encodes a receptor responsible for IGF-II degradation consist of differentially methylated DNA in association with multiple modifications on the associated histones. We review these epigenetic marks across various species during the evolution of IGF2R imprinting. Both IGF2 and IGF2R genesare imprinted in the mammal lineage that diverged from Monotremata approximately 150 million years ago. While IGF2 is consistently imprinted in all mammals following its divergence, IGF2R imprinting disappears in the Euarchonta lineage, including human species, approximately 75 million years ago. Differential DNA methylation marks on the two parental alleles correlate with imprinting in all imprinted genes including IGF2R. While the DNA methylation marks in the IGF2R promoter region 1 (DMR1) correlate with IGF2R allelic expression, the DNA methylation marks in the intron region 2 (DMR2) fail to correlate with IGF2R imprinting status in a number of species. Human IGF2R and mouse neuronal Igf2r are not imprinted despite the presence of DMR2. We have noted that human IGF2R is not imprinted in more than 100 informative samples including various tumor tissues. Furthermore, opossum (Marsupialia) IGF2R is consistently imprinted despite the absence of DMR2. These lines of evidence indicate that DNA methylation marks in DMR2 are neither necessary nor sufficient for consistent imprinting of IGF2R across species. Histone modification marks, however, correlate more consistently with the tissue-specific and species-specific imprinting status of IGF2R in human and mouse. Acetylated histone H3 and H4 and methylated lysine 4 of H3 (H3-K4Me) associate with transcriptionally active alleles while tri-methylated lysine 9 of H3 (H3-K9Me3) marks the silenced alleles. In the mouse, an antisense non-coding transcript called Air is transcribed from DMR2 on the paternal allele, and this imprinted transcript plays a central role in Igf2r imprinting. Mouse Igf2r imprinting depends on an Air RNA while the existence of AIR in other species is unknown. Overall, DNA methylation, histone acetylation, and histone methylation play a vital role in coordinating IGF2R allelic expression across all species. Rare monoallelic or skewed allelic expression of human IGF2R and their biological importance warrants further rigorous study.

Animals↗
PubMed2002

Histone methylation by the Drosophila epigenetic transcriptional regulator Ash1.

The establishment and maintenance of mitotic and meiotic stable (epigenetic) transcription patterns is fundamental for cell determination and function. Epigenetic regulation of transcription is mediated by epigenetic activators and repressors, and may require the establishment, 'spreading' and maintenance of epigenetic signals. Although these signals remain unclear, it has been proposed that chromatin structure and consequently post-translational modification of histones may have an important role in epigenetic gene expression. Here we show that the epigenetic activator Ash1 (ref. 5) is a multi-catalytic histone methyl-transferase (HMTase) that methylates lysine residues 4 and 9 in H3 and 20 in H4. Transcriptional activation by Ash1 coincides with methylation of these three lysine residues at the promoter of Ash1 target genes. The methylation pattern placed by Ash1 may serve as a binding surface for a chromatin remodelling complex containing the epigenetic activator Brahma (Brm), an ATPase, and inhibits the interaction of epigenetic repressors with chromatin. Chromatin immunoprecipitation indicates that epigenetic activation of Ultrabithorax transcription in Drosophila coincides with trivalent methylation by Ash1 and recruitment of Brm. Thus, histone methylation by Ash1 may provide a specific signal for the establishment of epigenetic, active transcription patterns.

Animals↗
PubMed2026

Epigenetic regulation of transgenes.

Gene therapy holds significant potential for treating genetic disorders, but the use of viral vectors is limited by factors such as immunogenicity, payload capacity, and high manufacturing costs. Nonviral gene delivery (NVGD) using plasmid DNA presents an attractive alternative; however, it typically provides a limited magnitude or duration of transgene expression. One potential reason for these shortcomings is the host cell's epigenetic regulation mechanisms, which can silence both viral and nonviral transgenes. Specifically, when foreign DNA enters the nucleus, it is detected by nuclear DNA sensors, such as IFI16, which initiate the assembly of a "restrictosome" or nuclear domain 10 (ND10) body. This multiprotein complex contains several components, such as PML, Speckled Proteins (e.g., SP100), DAXX, and ATRX that act as a scaffold for recruiting various epigenetic modifiers that subsequently deposit repressive histone modifications like H3K9me3 and H3K27me3 on the transgene chromatin. These marks induce DNA methylation and the subsequent condensation of plasmids or episomes into heterochromatin, which represses transgene expression. Alternatively, unmethylated CpG motifs in bacterial plasmid DNA can trigger innate immune responses in the cytosol, but this review will specifically focus on the detailed mechanisms of epigenetic regulation responsible for silencing plasmid DNA within the host cell nucleus. Addressing these nuclear defense mechanisms, potentially through strategies that manipulate DNA methylation or inhibit restrictosome activity, is crucial for advancing the development of safe, effective, and long-lasting plasmid viral and non-viral gene therapies.

Epigenesis, Genetic↗
PubMed2025

Epigenetic Regulation in Dilated Cardiomyopathy.

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.

Humans↗
PubMed2005

Retrovirus silencing and vector design: relevance to normal and cancer stem cells?

An obstacle confronting gene therapy in stem cells is transcriptional silencing of the vector. Here, we discuss recent data indicating that oncoretrovirus and lentivirus vectors are silenced by multiple epigenetic pathways that result in DNA methylation and histone modifications. Both vector types can be variegated in stem cells and expression is often extinguished during differentiation. We propose a novel model of retrovirus silencing in which epigenetic pathways compete to recruit histone deacetylases, de novo methyltransferases, histone H1 and MeCP2 to the provirus. These chromatin modifications may act in concert with heterochromatin at or near the integration site to establish silencing or variegation respectively. Retrovirus vector designs for stem cells should delete virus silencer elements, incorporate strong positive regulatory elements and insulators, and avoid non-mammalian reporter genes. In addition, cancer stem cells that continually repopulate a growing tumour may share silencing pathways with normal stem cells. Ultimately, optimized vector designs may prove to be valuable tools for gene therapy of both normal and cancer stem cells.

Epigenesis, Genetic↗
PubMed2006

Environmental and nutritional effects on the epigenetic regulation of genes.

Major efforts have been directed towards the identification of genetic mutations, their use as biomarkers, and the understanding of their consequences on human health and well-being. There is an emerging interest, however, in the possibility that environmentally-induced changes at levels other than the genetic information could have long-lasting consequences as well. This review summarises our current knowledge of how the environment, nutrition, and ageing affect the way mammalian genes are organised and transcribed, without changes in the underlying DNA sequence. Admittedly, the link between environment and epigenetics remains largely to be explored. However, recent studies indicate that environmental factors and diet can perturb the way genes are controlled by DNA methylation and covalent histone modifications. Unexpectedly, and not unlike genetic mutations, aberrant epigenetic alterations and their phenotypic effects can sometimes be passed on to the next generation.

Aging↗
PubMed2003

Methods and tips for the purification of human histone methyltransferases.

Recently developed biochemical techniques have enabled researchers to study histone modifications more easily and accurately. One of these modifications, histone lysine methylation, has been shown to be highly stable and to represent an epigenetic alteration. Extensive biochemical analyses have led to discoveries about the nature and functions of this modification, thus accelerating our understanding of this crucial epigenetic event. Here we describe basic methods for purification and biochemical analysis of lysine-directed, histone methyltransferases from HeLa cell-derived extracts. In the section on substrate preparation, we describe a simple method for the preparation of recombinant substrates, although we recommend using native substrates for initial detection of the activities. The purification protocols for several histone methyltransferases have been streamlined so that those researchers with a basic understanding of biochemistry can perform them. We also describe many tips and provide suggestions to avoid common pitfalls in the biochemical analysis of histone methyltransferases.

Amino Acid Sequence↗