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Results for “epigenetic modification”

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At least 793 records · Page 44Linked to original sources
PubMed2006

5-Aza-2'-deoxycytidine-mediated reductions in G9A histone methyltransferase and histone H3 K9 di-methylation levels are linked to tumor suppressor gene reactivation.

The epigenetic silencing of tumor suppressor genes is a common event during carcinogenesis, and often involves aberrant DNA methylation and histone modification of gene regulatory regions, resulting in the formation of a transcriptionally repressive chromatin state. Two examples include the antimetastatic, tumor suppressor genes, desmocollin 3 (DSC3) and MASPIN, which are frequently silenced in this manner in human breast cancer. Treatment of the breast tumor cell lines MDA-MB-231 and UACC 1179 with 5-aza-2'-deoxycytidine (5-aza-CdR) induced transcriptional reactivation of both genes in a dose-dependent manner. Importantly, DSC3 and MASPIN reactivation was closely and consistently linked with significant decreases in promoter H3 K9 di-methylation. Moreover, 5-aza-CdR treatment also resulted in global decreases in H3 K9 di-methylation, an effect that was linked to its ability to mediate dose-dependent, post-transcriptional decreases in the key enzyme responsible for this epigenetic modification, G9A. Finally, small interfering RNA (siRNA)-mediated knockdown of G9A and DNMT1 led to increased MASPIN expression in MDA-MB-231 cells, to levels that were supra-additive, verifying the importance of these enzymes in maintaining multiple layers of epigenetic repression in breast tumor cells. These results highlight an additional, complimentary mechanism of action for 5-aza-CdR in the reactivation of epigenetically silenced genes, in a manner that is independent of its effects on DNA methylation, further supporting an important role for H3 K9 methylation in the aberrant repression of tumor suppressor genes in human cancer.

Azacitidine↗
PubMed2005

Developmental regulation of Suz 12 localization.

Chromatin modifications are among the epigenetic alterations essential for genetic reprogramming during development. The Polycomb group (PcG) gene family mediates chromatin modifications that contribute to developmentally regulated transcriptional silencing. Trimethylation of histone H3 on lysine 27, mediated by a PcG protein complex consisting of Eed, Ezh2, and Suz12, is integral in differentiation, stem cell self-renewal, and tumorigenesis. Eed and Ezh2 are also implicated in the developmentally regulated silencing of the inactive X chromosome, as they are transiently enriched on the inactive X chromosome when X chromosome silencing is initiated. Here we analyze the dynamic localization of Suz12 during cellular differentiation and X-inactivation. Though Suz12 is a requisite member of the Eed/Ezh2 complexes, we found that Suz12 exhibits a notable difference from Ezh2 and Eed: while Ezh2 and Eed levels decrease during stem cell differentiation, Suz12 levels remain constant. Despite the differential regulation in abundance of Suz12 and Eed/Ezh2, Suz12 is also transiently enriched on the Xi during early stages of X-inactivation, and this accumulation is Xist RNA dependent. These results suggest that Suz12 may have a function that is not mediated by its association with Eed and Ezh2, and that this additional function is not involved in the regulation of X-inactivation.

Animals↗
PubMed2006

[Topology of chromosomes in somatic cells. Part 1].

The interphase cell nucleus is a highly compartmentalized structure in which chromosomes are located in separate, defined places called chromosome territories (CTs). Chromosome territories with interchromatin compartments (ICs) and the nuclear matrix determine the nuclear architecture. There is a connection between nuclear architecture and genome function. The topology of the chromosomes in the nuclei of somatic cells is summarized here. It is known that the size and location of chromosome territories are tissue specific and depend on the cell cycle and the size of the chromosomes and the density of the genes which are actively transcribed. The correlation between transcriptional activity, the level of chromatin structure, and the location of the chromatin domains is outlined. The tendency of the heterochromatin regions and the telomeres to associate and the influence of this on the nuclear architecture is highlighted. Some studies are focused on the indirect role of the elements of the nuclear matrix and the inner-nuclear membrane in maintaining the correct locations of chromosome territories. The role of interchromatin granule clusters (IGCs), which are located in the nuclear matrix and which remain active in nuclear processes connected with chromosome topology, is further described. The influence of cell differentiation on chromosome location is pointed out. The topology of chromosomes in evolutionarily distinct species is also mentioned in this review. The reciprocal location of the chromosome territories is probably one of the important epigenetical factors influencing correct genome function. The high level of the organization of chromatin and chromatin modifications create the unique epigenetic pattern of a particular cell type. This seems to indicate a critical role of the spatial genomic organization in regulating gene expression.

Animals↗
PubMed2002

Chromatin remodeling, histone modifications, and DNA methylation-how does it all fit together?

DNA methylation is important in the control of gene transcription and chromatin structure. The complexities of this process are just beginning to be elucidated in relationship to other epigenetic mechanisms. Exciting new research in the areas of histone methylation and chromatin remodeling make it clear just how important the connections between these various mechanisms and DNA methylation are for the control of chromosome structure and gene expression. Emerging evidence suggests that chromatin remodeling enzymes and histone methylation are essential for proper DNA methylation patterns. Other histone modifications, such as acetylation and phosphorylation, in turn, affect histone methylation and histone methylation also appears to be highly reliant on chromatin remodeling enzymes. This review will summarize what is likely only the beginning of a flood of new information that will ultimately link all epigenetic modifications of the mammalian genome. A model will also be put forth to account for how chromatin modifications lead to genomic DNA methylation patterns.

Acetylation↗
PubMed2005

CpG-binding protein (CXXC finger protein 1) is a component of the mammalian Set1 histone H3-Lys4 methyltransferase complex, the analogue of the yeast Set1/COMPASS complex.

CpG-binding protein (CXXC finger protein 1 (CFP1)) binds to DNA containing unmethylated CpG motifs and is required for mammalian embryogenesis, normal cytosine methylation, and cellular differentiation. Studies were performed to identify proteins that interact with CFP1 to gain insight into the molecular function of this protein. Immunoprecipitation and mass spectrometry reveal that human CFP1 associates with a approximately 450-kDa complex that contains the mammalian homologues of six of the seven components of the Set1/COMPASS complex, the sole histone H3-Lys4 methyltransferase in yeast. In vitro assays demonstrate that the human Set1/CFP1 complex is a histone methyltransferase that produces mono-, di-, and trimethylated histone H3 at Lys4. Confocal microscopy reveals that CFP1 and Set1 co-localize to nuclear speckles associated with euchromatin. A Set1 complex of reduced mass persists in murine embryonic stem cells lacking CFP1. These cells carry elevated levels of methylated histone H3-Lys4 and reduced levels of methylated histone H3-Lys9. Together with the previous finding of reduced levels of cytosine methylation, these data indicate that cells lacking CFP1 contain reduced levels of heterochromatin. Furthermore, ES cells lacking CFP1 exhibit a 4-fold excess of histone H3-Lys4 methylation following induction of differentiation, indicating that CFP1 restricts the activity of the Set1 histone methyltransferase complex. These results reveal a mammalian counterpart to the yeast Set1/COMPASS complex. The presence of CFP1 in this complex implicates this protein as a critical epigenetic regulator of histone modification in addition to cytosine methylation and reveals one mechanism by which this protein intersects with the epigenetic machinery.

Blotting, Western↗
PubMed2026

The interplay of epigenetic remodelling and transposon-mediated genomic instability in ageing and longevity.

Ageing and age-related diseases are the result of complex biological processes that progressively cause deterioration of cellular and tissue function. Among the key hallmarks of ageing are epigenetic alterations and genomic instability, both of which are closely interconnected and significantly contribute to the ageing process. The epigenome, encompassing both DNA and histone modifications, regulates gene expression and maintains genomic integrity throughout life. With age, these regulatory systems become dysregulated, leading to genome-wide changes in chromatin structure, histone modifications and the reactivation of transposable elements (TEs). TEs, typically silenced in heterochromatic regions, become active in aged cells, contributing to genomic instability, mutagenesis, inflammation and metabolic disruption. Despite their significant implications, the role of TEs in the ageing process remains underexplored, and the interplay between epigenomic remodelling and TE activity remains poorly understood. In this review, we explore the molecular mechanisms underlying epigenetic alterations and TE reactivation during ageing, the impact of these changes on genomic stability and the potential therapeutic interventions targeting this interplay. By deciphering the role of epigenetic modifications and TE derepression in the ageing process, we aim to highlight novel avenues for anti-ageing and pro-longevity strategies.

Aging↗
PubMed2004

Methods of epigenetic analysis.

Epigenetics encompasses heritable changes in DNA or its associated proteins except mutations in gene sequence. Many investigators in the field of epigenetics focus on histone modifications and DNA methylation, two molecular mechanisms that are often linked and interdependent. A variety of methods are applied to the study of epigenetic processes, and the past decade has witnessed an exponential increase in novel approaches to elucidate the molecular mysteries of epigenetic inheritance. This chapter summarizes some of the most contemporary methods used to study epigenetics presented throughout the book.

Chromatin↗
PubMed2006

Concise review: epigenetic mechanisms contribute to pluripotency and cell lineage determination of embryonic stem cells.

Epigenetic mechanisms, such as histone modifications and DNA methylation, have been shown to play a key role in the regulation of gene transcription. Results of recent studies indicate that a novel "bivalent" chromatin structure marks key developmental genes in embryonic stem cells (ESCs), wherein a number of untranscribed lineage-control genes, such as Sox1, Nkx2-2, Msx1, Irx3, and Pax3, are epigenetically modified with a unique combination of activating and repressive histone modifications that prime them for potential activation (or repression) upon cell lineage induction and differentiation. However, results of these studies also showed that a subset of lineage-control genes, such as Myf5 and Mash1, were not marked by these histone modifications, suggesting that distinct epigenetic mechanisms might exist for lineage-control genes in ESCs. In this review article, we summarize evidence regarding possible mechanisms that control these unique histone modifications at lineage-control gene loci in ESCs and consider their possible contribution to ESC pluripotency. In addition, we propose a novel "histone modification pulsing" model wherein individual pluripotent stem cells within the inner cell mass of blastocysts undergo transient asynchronous histone modifications at these developmental gene loci, thereby conferring differential responsiveness to environmental cues and morphogenic gradients important for cell lineage determination. Finally, we consider how these rapid histone modification exchanges become progressively more stable as ESCs undergo differentiation and maturation into specialized cell lineages.

Animals↗
PubMed2005

Epigenetic control of ovarian function: the emerging role of histone modifications.

The dynamic nature of the ovarian follicle makes it an ideal model to study the coordinated activation and inactivation of genes related to cell growth and differentiation. Much progress has been made in identifying transcription factors that promote the transcription of ovarian genes mediating gonadotropin action and steroidogenesis, but how these factors promote transcription in the context of chromatin is not well understood. Over the past 5 years, epigenetic regulation of ovarian genes through histone modifications has been the focus of an increasing number of studies. Several coactivators and corepressors associated with transcription factors are in fact histone acetyltransferases and histone deacetylases mediating the hyperacetylation and hypoacetylation of histones, respectively. Hyperacetylation of lysine residues in the core histone tails promotes chromatin alterations that favor transcription, whereas hypoacetylation of histones promotes gene silencing or repression. Not only does the acetylation status of the core histones determine whether chromatin remodeling occurs, but histone phosphorylation and methylation may serve equally important roles. For example, the combination of histone H3 phosphorylation and acetylation concertedly favors transcription. In addition, specific lysine methylations (e.g., K9 of histone H3) repress gene expression whereas other methylations promote gene expression. It is most likely the combination of histone modification events that regulate the initiation of transcription. Understanding how ovarian hormones control specific histone modifications will help us understand how follicular cells can switch from active gene pools governing cell proliferation to those gene groups controlling terminal differentiation. Progress in elucidating the ovarian specific regulation of histone modifying enzymes as well as identification of their target gene pools at different stages of the follicular cycle is expected in the next few years.

Acetylation↗
PubMed1996

[Disruption of genomic imprinting in human carcinogenesis].

Several lines of evidence have suggested that the accumulation of specific gene alterations such as the activation of proto-oncogenes and the silencing of suppressor genes is indispensable for tumorigenesis. In addition, recent molecular studies demonstrated that epigenetic alteration also have an important role in the initiation and progression of human cancers. In particular, the parent-of-origin specific gene modification, named genomic imprinting, has been demonstrated to play a causative roles in several human cancers including renal tumors of childhood. Although the precise mechanisms of genomic imprinting have not been clarified yet, it is obvious that the DNA methylation could be one of the key machinery to regulate differential expression of genes. In near future, the rapid advance in molecular genetics of human cancer will be expected in terms of epigenetic modification of cancer-associated genes.

Genomic Imprinting↗
PubMed2006

The necessity of a human epigenome project.

Epigenetics is one of the hottest topics in cancer research. We know that human tumors undergo a major disruption of their DNA methylation and histone modification patterns. The aberrant epigenetic landscape of the cancer cell is characterized by a massive genomic hypomethylation, CpG island promoter hypermethylation of tumor suppressor genes, an altered histone code for critical genes and a global loss of monoacetylated and trimethylated histone H4. But what we know is just a minimal percentage of the epigenetic 'earthquake' present in the transformed cell. We need to make an ambitious step to understand the DNA methylation and histone changes underlying tumorigenesis. The launching of an International Human Epigenome Project should be the response to this necessity.

CpG Islands↗
PubMed2004

Histone hypomethylation is an indicator of epigenetic plasticity in quiescent lymphocytes.

Post-translational modifications of histone amino termini are thought to convey epigenetic information that extends the coding potential of DNA. In particular, histone lysine methylation has been implicated in conveying transcriptional memory and maintaining lineage fidelity. Here an analysis of histone lysine methylation in quiescent (G(0)) and cycling lymphocytes showed that methylation of histone H3 at lysines 4 (H3K4), 9 (H3K9), 27 (H3K27) and histone H4 at lysine 20 is markedly reduced in resting B lymphocytes as compared with cycling cells. Quiescent B cells also lacked heterochromatin-associated HP1beta and Ikaros at pericentric chromatin and expressed low levels of Ezh2 and ESET histone methyl transferases (HMTases). Nuclei from resting B or T cells were approximately three times more efficiently reprogrammed in nuclear transfer assays than cells in which HMTase expression, histone methylation and HP1beta binding had been restored following mitotic stimulation. These results showing local and global changes in histone lysine methylation levels in vivo demonstrate that constitutive heterochromatin organization is modified in resting lymphocytes and suggest that histone hypomethylation is a useful indicator of epigenetic plasticity.

Animals↗
PubMed2005

Chromatin, epigenetics and stem cells.

Epigenetics is a term that has changed its meaning with the increasing biological knowledge on developmental processes. However, its current application to stem cell biology is often imprecise and is conceptually problematic. This article addresses two different subjects, the definition of epigenetics and chromatin states of stem and differentiated cells. We describe mechanisms that regulate chromatin changes and provide an overview of chromatin states of stem and differentiated cells. Moreover, a modification of the current epigenetics definition is proposed that is not restricted by the heritability of gene expression throughout cell divisions and excludes translational gene expression control.

Animals↗
PubMed2004

Differential regulation of P-selectin ligand expression in naive versus memory CD4+ T cells: evidence for epigenetic regulation of involved glycosyltransferase genes.

Lymphocytes are targeted to inflamed sites by specific "homing" and chemokine receptors. Most of them, including ligands for P- and E-selectin, are absent from naive CD4(+) T cells and become induced after activation and differentiation in effector/memory cells. Polarized effector cells are characterized by the rapid production of distinct cytokines upon restimulation. Their cytokine memory is in part controlled by epigenetic imprinting during differentiation. Here we ask whether a similar mechanism could regulate selectin ligand expression, mediating entry into inflamed sites, notably within the skin. We report that acquisition of selectin ligands by naive but not memory CD4(+) cells depends on progression through the G(1)/S phase of the cell cycle-a phase susceptible to modification of the chromatin structure. Cell-cycle arrest prevented transcriptional activation of glycosyltransferases involved in the generation of selectin ligands, suggesting that progression through the cell cycle is required to unlock their genes. Artificial DNA demethylation strongly increased the frequency of selectin ligand-expressing cells, suggesting that DNA methylation keeps transferase genes inaccessible in naive T cells. Due to these findings we propose that selectin-dependent inflammation-seeking properties are imprinted by epigenetic modifications upon T-cell differentiation into effector cells.

Animals↗
PubMed2006

Cyclophilin a protects Peg3 from hypermethylation and inactive histone modification.

Imprinted genes are expressed from only one of the parental alleles and are marked epigenetically by DNA methylation and histone modifications. Disruption of normal imprinting leads to abnormal embryogenesis, certain inherited diseases, and is associated with various cancers. In the context of screening for the gene(s) responsible for the alteration of phenotype in cyclophilin A knockdown (CypA-KD) P19 cells, we observed a silent paternally expressed gene, Peg3. Treatment of CypA-KD P19 cells with the DNA demethylating agent 5-aza-dC reversed the silencing of Peg3 biallelically. Genomic bisulfite sequencing and methylation-specific PCR revealed DNA hypermethylation in CypA-KD P19 cells, as the normally unmethylated paternal allele acquired methylation that resulted in biallelic methylation of Peg3. Chromatin immunoprecipitation assays indicated a loss of acetylation and a gain of lysine 9 trimethylation in histone 3, as well as enhanced DNA methyltransferase 1 and MBD2 binding on the cytosine-guanine dinucleotide (CpG) islands of Peg3. Our results indicate that DNA hypermethylation on the paternal allele and allele-specific acquisition of histone methylation leads to silencing of Peg3 in CypA-KD P19 cells. This study is the first demonstration of the epigenetic function of CypA in protecting the paternal allele of Peg3 from DNA methylation and inactive histone modifications.

Alleles↗
PubMed2005

Epigenetic regulation of Th1 and Th2 cell development.

All cells of the body, regardless of the tissue type, contain the same genetic material, but express this genetic material differently. Epigenetics is one process by which differential gene expression within a cell is regulated. Epigenetic mechanisms involve postsynthetic modifications to DNA and/or DNA-associated histones that do not change the DNA sequence itself, but which remodel chromatin, are passed along at each cell division, and occur during and after early development. The CD4+ T cell best represents a cell in which epigenetic mechanisms are used to affect mature cell physiology. As a naïve CD4+ T cell develops into either a Th1 or Th2 cell that secretes predominantly IFN-gamma or IL-4, respectively, the expression of one cytokine gene and the permanent silencing of the other is orchestrated using epigenetic mechanisms. Because there appears to be an association between Th1/Th2 cell immunity, behavior, and/or disease, it is possible that an environmentally induced epigenetic change that occurs during Th1/Th2 cell development could explain how certain Th1/Th2-associated conditions develop. This article will review basic epigenetic mechanisms and what is known about how these mechanisms influence cytokine gene expression in a naïve CD4+ T cell as it develops into a Th1 or Th2 cell.

Animals↗