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Results for “epigenetic modification”

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At least 1,207 records · Page 67Linked to original sources
PubMed2007

Histone deacetylase inhibitors increase neuronal differentiation in adult forebrain precursor cells.

Chromatin modification plays a key role in fate decision of neural stem cells. Here, we explored the impact of epigenetic remodelling onto neuronal fate determination using specific inhibitors of histone deacetylases (iHDAC). Adult subventricular zone (SVZ) precursor cells were expanded as neurospheres and treated in vitro with second generation iHDAC MS-275, M344 and suberoylanilide hydroxamic acid (SAHA). All tested compounds revealed a significant increase of betaIII-tubulin positive neurons (ranging from 258 to 431%) in a concentration-dependent manner. The number of oligodendrocytes was decreased by almost 50%, accompanied by a reduction of Olig2 mRNA expression. In contrast, astrocyte quantity remained unaffected after iHDAC treatment. Both control and iHDAC treated cells expressed markers of mature GABAergic and dopaminergic neurons. Increased expression levels of NeuroD, Cyclin D2 and B-lymphocyte translocation gene 3 (Btg3) point to a shift towards neuronal fate determination targeted by HDAC inhibitors.

Age Factors↗
PubMed2004

Sin3: a flexible regulator of global gene expression and genome stability.

SIN3 was first identified genetically as a global regulator of transcription. Sin3 is a large protein composed mainly of protein-interaction domains, whose function is to provide structural support for a heterogeneous Sin3/histone deacetylase (HDAC) complex. The core Sin3/HDAC complex is conserved from yeast to man and consists of eight proteins. In addition to HDACs, Sin3 can sequester other enzymatic functions, including nucleosome remodeling, DNA methylation, N-acetylglucoseamine transferase activity, and histone methylation. Since the Sin3/HDAC complex lacks any DNA-binding activity, it must be targeted to gene promoters by interacting with DNA-binding proteins. Although most research on Sin3 has focused on its role as a corepressor, mounting evidence suggests that Sin3 can also positively regulate transcription. Furthermore, Sin3 is key to the propagation of epigenetically silenced domains and is required for centromere function. Thus, Sin3 provides a platform to deliver multiple combinations modifications to the chromatin, using both sequence-specific and sequence-independent mechanisms.

Chromatin↗
PubMed1980

r- and K-tactics in the evolution of protist developmental systems: cell and genome size, phenotype diversifying selection, and cell cycle patterns.

I outline the significance for protist evolution of the r-, K-selection spectrum,, and of my earlier theory that the most fundamental way organisms adapt to this spectrum is by evolutionary variations in their cell volumes, cell growth rates and genome sizes. Then I introduce the concept of phenotype diversifying selection; this refers to those selective forces which favour an increase in the number of phenotypes produced during a single life cycle by an organism's genotype and epigenetic system. These ideas are then used to discuss the evolution of protist development, with special reference to modifications of the cell cycle whose evolutionary causes and consequences can be related to K-selection for large size and r-selection for rapid reproduction. The significance of multiple fission, syncytia, multicellularity, nuclear dimorphism plus polyploidy, and reversible polyploidy, is treated in detail. Predictions are made of the effects of these different developmental patterns on genome size and the distribution and amounts of nucleoskeletal RNA and heterochromatin. I suggest that heterochromatin exists primarily because of phenotype diversifying selection for differing nuclear volumes. The possibility of applying these ideas to other cell properties like mitotic or cytokinetic mechanisms is also briefly discussed.

Animals↗
PubMed2000

Multiple links between the NuA4 histone acetyltransferase complex and epigenetic control of transcription.

NuA4 is an essential histone H4/H2A acetyltransferase complex that interacts with activators and stimulates transcription in vitro. We have identified three novel NuA4 subunits: Act3/Arp4, an actin-related protein implicated in epigenetic control of transcription, Act1, and Epl1, a protein homologous to Drosophila Enhancer of Polycomb. Act3/Arp4 binds nucleosomes in vitro and is required for NuA4 integrity in vivo. Mutations in ACT3 and acetyltransferase-encoding ESA1 cause gene-specific transcription defects. Accordingly, NuA4 is localized in precise loci within the nucleus and does not overlap with the silent chromatin marker Sir3. These data along with the known epigenetic roles of Act3/Arp4 and homologs of Epl1 and Esa1 strongly support an essential role for chromatin structure modification by NuA4 in transcription regulation in vivo.

Acetyltransferases↗
PubMed2003

Histone deacetylases.

Post-translational modification of the histones of chromatin has a fundamental role in regulating gene expression. Enzymes involved in these epigenetic events include histone deacetylases (class I and class II), which can be inhibited by a structurally diverse group of small molecules. These histone deacetylase inhibitors induce growth arrest, differentiation and/or apoptosis of cancer cells in vitro and in vivo. Results of clinical trials with several of these agents have indicated that they are well tolerated at doses that have anti-tumour activity.

Animals↗
PubMed2000

Epigenetic mechanisms of chemical carcinogenesis.

Chemically induced cancer is a multi-step process involving damage to the genome initially followed by clonal expansion of the DNA damaged cell eventually leading to a neoplasm. Chemical carcinogens have been shown to impact at all of the stages of the tumorigenesis process. It has become apparent that chemical and physical agents that induce cancer may do so through several different cellular and molecular mechanisms. Epigenetic (nongenotoxic) chemical carcinogens are those agents that function to induce tumor formation by mechanisms exclusive of direct modification or damage to DNA. These agents appear to modulate cell growth and cell death and exhibit dose response relationships between exposure and tumor formation. The exact and/or exclusive mechanisms by which these agents function have not been established, however, changes in cell growth regulation and gene expression are important to tumor formation. This review focuses on several potential mechanisms and cellular processes that may be involved in nongenotoxic chemical carcinogenesis.

Animals↗
PubMed2006

Nonadditive regulation of FRI and FLC loci mediates flowering-time variation in Arabidopsis allopolyploids.

Allopolyploidy is formed by combining two or more divergent genomes and occurs throughout the evolutionary history of many plants and some animals. Transcriptome analysis indicates that many genes in various biological pathways, including flowering time, are expressed nonadditively (different from the midparent value). However, the mechanisms for nonadditive gene regulation in a biological pathway are unknown. Natural variation of flowering time is largely controlled by two epistatically acting loci, namely FRIGIDA (FRI) and FLOWERING LOCUS C (FLC). FRI upregulates FLC expression that represses flowering in Arabidopsis. Synthetic Arabidopsis allotetraploids contain two sets of FLC and FRI genes originating from Arabidopsis thaliana and A. arenosa, respectively, and flower late. Inhibition of early flowering is caused by upregulation of A. thaliana FLC (AtFLC) that is trans-activated by A. arenosa FRI (AaFRI). Two duplicate FLCs (AaFLC1 and AaFLC2) originating from A. arenosa are expressed in some allotetraploids but silenced in other lines. The expression variation in the allotetraploids is associated with deletions in the promoter regions and first introns of A. arenosa FLCs. The strong AtFLC and AaFLC loci are maintained in natural Arabidopsis allotetraploids, leading to extremely late flowering. Furthermore, FLC expression correlates positively with histone H3-Lys4 methylation and H3-Lys9 acetylation and negatively with H3-Lys9 methylation, epigenetic marks for gene activation and silencing. We provide evidence for interactive roles of regulatory sequence changes, chromatin modification, and trans-acting effects in natural selection of orthologous FLC loci, which determines the fate of duplicate genes and adaptation of allopolyploids during evolution.

Acetylation↗
PubMed2004

Modulation of renal disease in MRL/lpr mice by suberoylanilide hydroxamic acid.

Epigenetic regulation of gene expression is involved in the development of many diseases. Histone acetylation is a posttranslational modification of the nucleosomal histone tails that is regulated by the balance of histone deacetylases and histone acetyltransferases. Alterations in the balance of histone acetylation have been shown to cause aberrant expression of genes that are a hallmark of many diseases, including systemic lupus erythematosus. In this study, we determined whether suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor: 1) inhibits inflammatory mediator production in vitro and 2) modulates lupus progression in vivo. Mesangial cells isolated from 10-wk-old MRL/lpr mice were stimulated with LPS/IFN-gamma and incubated with SAHA. TNF-alpha, IL-6, NO, and inducible NO synthase expression were inhibited by SAHA. We then treated MRL/lpr mice with daily injections of SAHA from age 10 to 20 wk. The animals treated with SAHA had decreased spleen size and a concomitant decrease in CD4-CD8- (double-negative) T cells compared with controls. Serum autoantibody levels and glomerular IgG and C3 deposition in SAHA-treated mice were similar to controls. In contrast, proteinuria and pathologic renal disease were significantly inhibited in the mice receiving SAHA. These data indicate that SAHA blocks mesangial cell inflammatory mediator production in vitro and disease progression in vivo in MRL/lpr mice.

Adjuvants, Immunologic↗
PubMed2003

Cancer and epigenesis: a developmental perspective.

Traditionally, molecular geneticists have studied the genome, that is, DNA. This has included its sequencing, with identification of promoters, enhancers, introns, exons, and mutations. During the last 10 to 15 years, it has become clear that this study of "naked" DNA imposed major limitations on our understanding of gene regulation, and that DNA must be studied in conjunction with its protein backbone (chromatin). This new vision has shown that chromatin is a very dynamic molecule, and that changes in DNA methylation, in histones leg, their localization, density, and whether they are acetylated, methylated, phosphorylated and/or ubiquitinated), and in the Polycomb-Trithorax equilibrium are all crucial for the control of gene expression. Furthermore, it was found that like DNA, chromatin-related proteins and DNA methylation are generally passed on unchanged from one cell to its daughters. Thus, gene expression is partly controlled through chromatin modifications that are transmitted from one cell to all its descendants. Such a control is referred to as "epigenetic," as the DNA sequence is not altered. Hence, these epigenetic "marks" can be erased in the early embryo, rendering these cells totipotent. This chapter presents a basic overview of epigenesis in the control of normal embryonal cell differentiation, including imprinting. Similarities between embryonal and cancer cells are highlighted, and the potential impact of chemotherapy aimed at epigenetic mechanisms is reviewed.

Alleles↗
PubMed2025

A Protocol for Detecting DNA Methylation Changes at CpG Sites of Stemness-Related Genes in Aging Stem Cells.

Aging adversely affects the self-renewal and differentiation capabilities of stem cells, which impairs tissue regeneration as well as the homeostasis. Epigenetic mechanisms, specifically DNA methylation, play a key role in the maintenance of pluripotency in stem cells and regulation of pluripotency-related gene expression. Age-related modifications in methylation patterns could influence the expression of genes critical for stem cell potency maintenance, including transcription factors Nanog and Sox2. The following chapter describes a step-by-step bisulfite sequencing protocol for detection of methylation changes in the aging stem cells and provides valuable insights into the stem cells epigenetic profile. Further, the methodology describes the steps of genomic DNA extraction, bisulfite conversion, real-time PCR amplification, and sequencing for an in-depth view of the epigenetic profile derived from aging stem cells.

DNA Methylation↗
PubMed2003

Methyl-CpG binding proteins identify novel sites of epigenetic inactivation in human cancer.

Methyl-CpG binding proteins (MBDs) mediate histone deacetylase-dependent transcriptional silencing at methylated CpG islands. Using chromatin immunoprecitation (ChIP) we have found that gene-specific profiles of MBDs exist for hypermethylated promoters of breast cancer cells, whilst a common pattern of histone modifications is shared. This unique distribution of MBDs is also characterized in chromosomes by comparative genomic hybridization of immunoprecipitated DNA and immunolocalization. Most importantly, we demonstrate that MBD association to methylated DNA serves to identify novel targets of epigenetic inactivation in human cancer. We combined the ChIP assay of MBDs with a CpG island microarray (ChIP on chip). The scenario revealed shows that, while many genes are regulated by multiple MBDs, others are associated with a single MBD. These target genes displayed methylation- associated transcriptional silencing in breast cancer cells and primary tumours. The candidates include the homeobox gene PAX6, the prolactin hormone receptor, and dipeptidylpeptidase IV among others. Our results support an essential role for MBDs in gene silencing and, when combined with genomic strategies, their potential to 'catch' new hypermethylated genes in cancer.

5-Methylcytosine↗
PubMed2007

Multiple binding of methyl-CpG and polycomb proteins in long-term gene silencing events.

Epigenetic regulation is involved in the maintenance of long-term silencing phenomena, such as X-inactivation and genomic imprinting in mammals. Gene repression is mediated by several mechanisms, such as histone modifications, DNA methylation, and recruitment of Polycomb proteins. To understand the mechanistic relationships between these mechanisms for stable gene silencing, we analyzed the mechanisms of X- and Y-inactivation of the PAR2 gene SYBL1, previously showed to be regulated by concerted epigenetic mechanisms. Maintenance of stable repression occurs via the recruitment of both MBDPs and PRC2 complexes to SYBL1 promoter. Their binding is equally sensitive to defective DNA methylation seen in cells derived from ICF syndrome patients. Multiple occupancy is a feature shared within long-term repressed genes, such as the X-inactivated PGK1 and the imprinted IGF2. MBD2, MBD3, and MeCP2 occupy SYBL1 promoter simultaneously, as revealed by sequential ChIP. We did not find this co-occurring binding when looked for members of PRC2 complex together with any of the methyl-binding proteins. Furthermore, in co-transfection assays, MECP2 can silence methylated SYBL1 promoter, whereas the mutated protein fails. However, RNA interference of endogenous MECP2 does not induce the expression of the inactive SYBL1 alleles, suggesting that its silencing activity can be replaced by the other methyl-binding proteins. Our data suggest that maintenance of long-term silencing involves multiple layers of epigenetic control functionally redundant. PRC2 and MBD proteins could collaborate to different phases of this process, the former possibly recruiting DNMTs to the silenced promoters, the latter dictating the lock of the transcription.

Cell Line↗
PubMed2007

Methyl deficiency, alterations in global histone modifications, and carcinogenesis.

The methyl-deficient model of endogenous hepatocarcinogenesis in rodents is unique in that dietary omission rather than the addition of chemical carcinogens leads to tumor formation. Thus, the biochemical and molecular events predisposing to cancer in this model result from chronic metabolic stress and provide an ideal model system to study progressive alterations that occur during carcinogenesis. Moreover, epigenetic alterations imposed by this diet are believed to be 1 of the main mechanisms responsible for malignant transformation of rat liver cells. In this study we examined the changes in global histone modification patterns in liver during hepatocarcinogenesis induced by methyl deficiency. Feeding animals the methyl-deficient diet (MDD) led to progressive loss of histone H4 lysine 20 trimethylation (H4K20me3), H3 lysine 9 trimethylation (H3K9me3), and histone H3 lysine 9 (H3K9ac) and histone H4 lysine 16 (H4K16ac) acetylation. A considerable decrease of H4K20me3 and H3K9ac was also detected in liver tumors induced by MDD. In contrast, liver tumors displayed an increase in H3K9me3 and H4K16ac. To determine the possible mechanism of alterations of histone modifications, we analyzed the expression of histone-modifying enzymes in liver during hepatocarcinogenesis. The expression of Suv4-20h2 and RIZ1 histone methyltransferases (HMTs) steadily decreased along with the development of liver tumors and reached its lowest level in tumor tissue, whereas the expression of Suv39-h1 HMT and histone acetyltransferase 1 (HAT1) substantially increased in tumors. These results illustrate the complexity and importance of histone modification changes in the etiology of hepatocarcinogenesis induced by MDD.

Animals↗
PubMed2003

Promoter-restricted H3 Lys 4 di-methylation is an epigenetic mark for monoallelic expression.

Methylation of histone tails has been implicated in long-term epigenetic memory. Methylated H3 Lys 4 (K4) is a generally conserved mark for euchromatic, transcriptionally active regions, although the effect of this modification is likely also to depend on its distribution both within the euchromatic region and more specifically within a given gene. Here we describe a profile of H3K4 di-methylation that is specific for monoallelically expressed genes. Both X-linked genes subject to X-inactivation and autosomal imprinted genes have di-methylated H3K4 restricted to their promoter regions. In contrast, high levels of H3K4 di-methylation are found in both promoters and exonic parts of autosomal genes and of X-linked genes that escape X-inactivation. We suggest that this pattern of promoter restricted H3 Lys 4 di-methylation, already present in totipotent cells, is causally related to the long-term programming of allelic expression and provides an epigenetic mark for monoallelically expressed genes.

Alleles↗
PubMed2006

Epigenetic characterization of the early embryo with a chromatin immunoprecipitation protocol applicable to small cell populations.

Chromatin immunoprecipitation (ChIP) defines the genomic distribution of proteins and their modifications but is limited by the cell numbers required (ideally >10(7)). Here we describe a protocol that uses carrier chromatin and PCR, 'carrier' ChIP (CChIP), to permit analysis of as few as 100 cells. We assayed histone modifications at key regulator genes (such as Nanog, Pou5f1 (also known as Oct4) and Cdx2) by CChIP in mouse embryonic stem (ES) cells and in inner cell mass (ICM) and trophectoderm of cultured blastocysts. Activating and silencing modifications (H4 acetylation and H3K9 methylation) mark active and silent promoters as predicted, and we find close correlation between values derived from CChIP (1,000 ES cells) and conventional ChIP (5 x 10(7) ES cells). Studies on genes silenced in both ICM and ES cells (Cdx2, Cfc1, Hhex and Nkx2-2, also known as Nkx) show that the intensity of silencing marks is relatively diminished in ES cells, indicating a possible relaxation of some components of silencing on adaptation to culture.

Animals↗
PubMed2025

Nanoscale Epigenetic Profiling of Colorectal Cancer Cell-Derived Exosomes via Single-Vesicle Nanoscopy.

Exosomes play critical roles in cancer diagnosis and treatment as they carry molecular information that reflects the epigenetic state of their parent cells. For the first time, nanoscale epigenetic profiling of individual exosomes derived from colorectal cancer cell lines is demonstrated via photo-induced force microscopy (PiFM). Exosomes from three cell lines with distinct CpG island methylator phenotype (CIMP) status are analyzed at the single-vesicle level. The nano-IR method provides simultaneous high-resolution topographical and spectroscopic data, revealing detailed vibrational signatures that distinguish CIMP-high (HCT116 and HT29) exosomes from CIMP-negative (SW480) ones. Notably, exosomes from CIMP-high cells exhibit red-shifted amide I and nucleic acid region compared to those from CIMP-negative cells, a shift attributed to increased 5-methylcytosine (5mC) modifications, as verified by quantum chemical calculations. Furthermore, these measurements reveal heterogeneity among individual exosomes, suggesting the presence of distinct subpopulations with unique epigenetic profiles, demonstrating the importance of single-vesicle resolution to detect molecular variations that remain obscured in ensemble studies. These findings present the potential of PiFM-based single-vesicle analysis to identify epigenetic markers in exosomes, laying the groundwork for its application in refined cancer diagnostics and targeted therapeutic strategies.

Humans↗