Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “epigenetic modification”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,225 records · Page 68Linked to original sources
PubMed2006

Abnormal histone acetylase and deacetylase expression and function in lung inflammation.

Post-translational modifications in DNA and histone proteins are heritable changes that are not coded for in the DNA sequence itself but play an important role in the control of gene expression. These modifications include histone acetylation, methylation, ubiquitination, sumoylation and phosphorylation. These changes are not only critical for generating diversity of cell types during mammalian development, but are also important for maintaining the stability and integrity of the expression profiles of different cell types. Until recently, the study of human disease has focused on genetic mechanisms rather than on non-coding events. However, it is becoming increasingly clear that altered patterns of histone modifications can lead to several major pathologies. This review focuses on histone acetylation and its role in inflammatory gene expression. Interestingly, the expression and activity of enzymes that regulate this modification have been reported to be abnormal in the airways of patients with respiratory disease. Histone modifications, despite being heritable and stably maintained, are also potentially reversible and there is scope for the development of "epigenetic therapies" for disease.

Animals↗
PubMed2006

Chromatin control and cancer-drug discovery: realizing the promise.

Recent years have seen major advances in elucidating the complexity of chromatin and its role as an epigenetic regulator of gene expression in eukaryotes. We now have a basic understanding of chromatin control and the enzymatic modifications that impart diverse regulatory cues to the functional activity of the genome. Most importantly, although research into chromatin has uncovered fascinating insights into the control of gene expression, it has also generated a large body of information that is being harnessed to develop new therapeutic modalities for treating cancer. Here, we discuss recent advances that support the contention that future generations of chromatin-modulating drugs will provide a significant group of new, mechanism-based therapeutics for cancer.

Antineoplastic Agents↗
PubMed2006

Crystal structure and mechanism of human lysine-specific demethylase-1.

The reversible methylation of specific lysine residues in histone tails is crucial in epigenetic gene regulation. LSD1, the first known lysine-specific demethylase, selectively removes monomethyl and dimethyl, but not trimethyl modifications of Lys4 or Lys9 of histone-3. Here, we present the crystal structure of LSD1 at 2.9-A resolution. LSD1 forms a highly asymmetric, closely packed domain structure from which a long helical 'tower' domain protrudes. The active site cavity is spacious enough to accommodate several residues of the histone tail substrate, but does not appear capable of recognizing the different methylation states of the substrate lysine. This supports the hypothesis that trimethylated lysine is chemically rather than sterically discriminated. We present a biochemical analysis of LSD1 mutants that identifies crucial residues in the active site cavity and shows the importance of the SWIRM and tower domains for catalysis.

Binding Sites↗
PubMedDate not supplied

Understanding and modulating ageing.

Ageing is characterized by a progressive accumulation of molecular damage in nucleic acids, proteins and lipids. The inefficiency and failure of maintenance, repair and turnover pathways is the main cause of age-related accumulation of damage. Research in molecular gerontology is aimed at understanding the genetic and epigenetic regulation of survival and maintenance mechanisms at the levels of transcription, post-transcriptional processing, post-translational modifications, and interactions among various gene products. Concurrently, several approaches are being tried and tested to modulate ageing in a wide variety of organisms. The ultimate aim of such studies is to improve the quality of human life in old age and prolong the health-span. Various gerontomodulatory approaches include gene therapy, hormonal supplementation, nutritional modulation and intervention by free radical scavengers and other molecules. A recent approach is that of applying hormesis in ageing research and therapy, which is based on the principle of stimulation of maintenance and repair pathways by repeated exposure to mild stress. A combination of molecular, physiological and psychological modulatory approaches can realize "healthy ageing" as an achievable goal in the not-so-distant future.

Aging↗
PubMed2005

Assembly of variant histones into chromatin.

Chromatin can be differentiated by the deposition of variant histones at centromeres, active genes, and silent loci. Variant histones are assembled into nucleosomes in a replication-independent manner, in contrast to assembly of bulk chromatin that is coupled to replication. Recent in vitro studies have provided the first glimpses of protein machines dedicated to building and replacing alternative nucleosomes. They deposit variant H2A and H3 histones and are targeted to particular functional sites in the genome. Differences between variant and canonical histones can have profound consequences, either for delivery of the histones to sites of assembly or for their function after incorporation into chromatin. Recent studies have also revealed connections between assembly of variant nucleosomes, chromatin remodeling, and histone post-translational modification. Taken together, these findings indicate that chromosome architecture can be highly dynamic at the most fundamental level, with epigenetic consequences.

Animals↗
PubMed1999

The cadherin-catenin system: implications for growth and differentiation of endocrine tissues.

Cell-cell adhesion, as mediated by the cadherin-catenin system, is a prerequisite for normal cell function and the preservation of tissue integrity. With recent progress in our understanding, beta-catenin as a component of a complex signal transduction pathway may serve as a common switch in central processes that regulate cellular differentiation and growth. The function of the cadherin-catenin system in cell adhesion as well as in intracellular signaling, appears to be subjected to multifactorial control by a variety of different mechanisms, and data on a hormonal control of these signaling pathways, even though scarce to date, suggest an important regulatory influence in many cellular systems. Loss of E-cadherin-catenin function was described in many tumors along with an increased invasiveness and a decreased prognosis of many carcinomas, including tumors of endocrine glands and their target systems, and a causal role of this loss-of-function in the multifactorial process of tumorigenesis was recently proven in genetic mouse models. Modification of E-caderin-catenin function in endocrine and nonendocrine tumors may involve germline and somatic gene mutations, epigenetic mechanisms such as gene silencing due to promotor-hypermethylation, and posttranscriptional events, likely to be involved in many endocrine tissues and their target organs. Such events may converge on nuclear activation of oncogenes such as c-myc by the beta-catenin/TCF4 complex. The expression and functional status of the components of the cadherin-catenin system may serve as prognostic markers for endocrine and nonendocrine tumors. The frequent involvement of functional dysregulation in many tumors raises hopes that better definition of the regulation of all components of the cadherin-catenin system and their response to extracellular modulators may eventually lead to new therapeutic approaches for these tumors and help to prevent, more specifically, growth, invasion, and metastasis of these carcinomas.

Animals↗
PubMed2006

Gene methylation in thyroid tumorigenesis.

Aberrant gene methylation plays an important role in human tumorigenesis, including thyroid tumorigenesis. Many tumor suppressor genes are aberrantly methylated in thyroid cancer, and some even in benign thyroid tumors, suggesting a role of this epigenetic event in early thyroid tumorigenesis. Methylation of some of these genes tends to occur in certain types of thyroid cancer and is related to specific signaling pathways. For example, methylation of PTEN and RASSF1A genes occurs mostly in follicular thyroid cancer, and its tumorigenic role may be related to the phosphatidylinositol 3-kinase/Akt signaling pathway, whereas methylation of genes for tissue inhibitor of metalloproteinase-3, SLC5A8, and death-associated protein kinase occurs in papillary thyroid cancer and is related to the BRAF/MAPK kinase/MAPK pathway. Methylation of thyroid-specific genes, such as those for sodium/iodide symporter and thyroid-stimulating hormone receptor, is also common in thyroid cancer. Although its tumorigenic role is not clear, methylation, and hence silencing, of these thyroid-specific genes is a cause for the failure of clinical radioiodine treatment of thyroid cancer. Unlike gene methylation, histone modifications have been relatively poorly investigated in thyroid tumors. Future studies need to emphasize the mechanistic aspects of these two types of epigenetic alterations to uncover new molecular mechanisms in thyroid tumorigenesis and to provide novel therapeutic targets for thyroid cancer.

Animals↗
PubMedDate not supplied

DNA methylation and epigenetic mechanisms.

Genes are essential for the transmission of genetic information from generation to generation, and this mechanism of inheritance is fully understood. Genes are also essential for unfolding the genetic program for development, but the rules governing this process are obscure. Epigenetics comprises the study of the switching on and off of genes during development, the segregation of gene activities following somatic cell division, and the stable inheritance of a given spectrum of gene activities in specific cells. Some of these processes may be explained by DNA modification, particularly changes in the pattern of DNA methylation and the heritability of that pattern. There is strong evidence that DNA methylation plays an important role in the control of gene activity in cultured mammalian cells, and the properties of a CHO mutant strain affected in DNA methylation are described. Human diploid cells progressively lose cytosine methylation during serial subculture, and this may be related to their in vitro senescence. There is also evidence that DNA modifications can be inherited through the germ line. Classical genetics is based on the study of all types of change in DNA base sequence, but the rules governing the activity of genes by epigenetic mechanisms are necessarily different. Their elucidation will depend both on a theoretical framework for development and on experimental studies at the molecular, chromosomal, and cellular levels.

Animals↗
PubMedDate not supplied

Nucleic acid-based marker approaches to urologic cancers.

There are numerous molecular modifications known to occur in cancer. New nucleic acid-based biomarkers provide a unique approach to patient management in urologic oncology. Malignant transformation of a normal cell requires a series of epigenetic and genetic changes or "hits." Epigenetics produced by deoxyribonucleic acid methylation, adding a methyl group to the fifth position of cytosine within CpG dinucleotides, are important players in deoxyribonucleic acid repair, genome instability, and regulation of chromatin structure. Genetic alterations in cancer can include mutations, chromosome deletions, insertions, amplifications, and translocations. In addition, the modifications of telomeres are critical to the maintenance of chromatin structure, transcription, and cell function in cancer. We review only nucleic acid-based molecular biomarkers in urologic oncology that can assist the clinician in establishing the diagnosis of disease, or that can predict the behavior of the disease or the patient's survival.

Biomarkers, Tumor↗
PubMed2005

Developmental regulation of the beta-globin gene locus.

The beta-globin genes have become a classical model for studying regulation of gene expression. Wide-ranging studies have revealed multiple levels of epigenetic regulation that coordinately ensure a highly specialised, tissue- and stage-specific gene transcription pattern. Key players include cis-acting elements involved in establishing and maintaining specific chromatin conformations and histone modification patterns, elements engaged in the transcription process through long-range regulatory interactions, transacting general and tissue-specific factors. On a larger scale, molecular events occurring at the locus level take place in the context of a highly dynamic nucleus as part of the cellular epigenetic programme.

Animals↗
PubMed2001

DNA methylation and epigenetic inheritance in plants and filamentous fungi.

Plants and filamentous fungi share with mammals enzymes responsible for DNA methylation. In these organisms, DNA methylation is associated with gene silencing and transposon control. However, plants and fungi differ from mammals in the genomic distribution, sequence specificity, and heritability of methylation. We consider the role that transposons play in establishing methylation patterns and the epigenetic consequences of their perturbation.

DNA Methylation↗
PubMed2005

Epigenetic silencing of manganese superoxide dismutase (SOD-2) in KAS 6/1 human multiple myeloma cells increases cell proliferation.

The generation of reactive oxygen species (ROS) by mitochondrial electron transport chain (ETC) and oxidative phosphorylation activity, has been linked to modifications of multiple molecular processes, including lipid peroxidation, signaling pathway and transcription factor modulation, and oxidative damage to DNA. Oxidative damage by endogenous ROS has been associated with the etiology of various pathological states. There are numerous reports that levels of manganese superoxide dismutase enzyme (MnSOD), an antioxidant enzyme responsible for the attenuation of ROS, are lowered in cancer cells, but the reasons for this reduction are poorly defined. Epigenetic silencing of genes involved in tumor suppression and DNA repair is known to occur in a variety of malignant cell types. Here we report that in the human multiple myeloma cell line KAS 6/1, the SOD-2 gene, encoding manganese superoxide dismutase, is epigenetically silenced as a result of promoter hypermethylation. The DNA methyltransferase inhibitor Zebularine reverses SOD-2 promoter methylation, increasing gene expression and enzyme levels. Infection of KAS 6/1 cells with a recombinant adenovirus carrying the MnSOD cDNA reduced the cell proliferation rate by approximately one-half, confirming the detrimental effects of epigenetic silencing of SOD-2 expression.

Cell Line, Tumor↗
PubMed1993

The role of histones and their modifications in the informative content of chromatin.

It is traditionally accepted that the DNA sequence cannot by itself explain all the mechanisms necessary for the development of living beings, especially in eukaryotes. Indeed part of the information used in these processes is stored in other ways, generally called 'epigenetic', whose molecular mechanisms are mostly unknown. The ultimate explanation for them might reside in the non-DNA moiety of chromatin which may play an active role in heredity ('chromatin information'). Histones are the universal structural component of chromatin. However, recent studies strongly suggest that histones, and their modifications--especially the reversible acetylation of lysines--may act as a recognition signal for regulatory proteins and they may participate, for this reason, in gene regulation. This type of information could be maintained through its replication and, ultimately, it could form the molecular basis of certain processes related to the development of the eukaryotic organisms.

Acetylation↗
PubMed2005

Disruption of the Fanconi anemia/BRCA pathway in sporadic cancer.

An increasing number of studies provide evidences linking disruption of Fanconi anemia/BRCA cascade with sporadic cancers. Given that this pathway plays essential roles in response to the DNA interstrand cross-links, these cancers are expected to be chemosensitive to cross-link based therapy. In the present mini-review we expand the spectrum of possibilities for FA/BRCA disruption and review some works describing functional upstream and downstream events linking disruption of the FA/BRCA pathway to sporadic cancer. This may involve but not limited to epigenetic silencing of the FA-core complex or BRCA1/2, mutations of one or several FA-BRCA genes or modification of encoded products. All this may serve as a platform for occurrence, development and treatment of sporadic cancers and therefore deserves to be in the focus of new research directions.

Chromosome Aberrations↗
PubMed2006

Clinical features associated to refractory obsessive-compulsive disorder.

UNLABELLED: Some patients with obsessive-compulsive disorder (OCD) exhibit an unsatisfactory reduction in symptom severity despite being treated with all the available therapeutic alternatives. The clinical variables associated with treatment-refractoriness in OCD are inconsistently described in the literature. METHODS: To investigate factors associated with treatment-refractoriness of patients with OCD, we conducted a case-control study, comparing 23 patients with treatment-refractory OCD to 26 patients with treatment-responding OCD. RESULTS: The factors associated with refractoriness of OCD were higher severity of symptoms since the onset of OCD (p<0.001), chronic course (p=0.003), lack of a partner (p=0.037), unemployment (p=0.025), low economic status (p=0.015), presence of obsessive-compulsive symptoms of sexual/religious content (p=0.043), and higher scores on family accommodation (p<0.001). Only the three latter variables remained significantly associated with treatment-refractoriness after regression analyses. LIMITATIONS: small sample size, the biases and drawbacks inherent to a case-control study, and the inclusion criteria used to define the study groups may have limited the generalisation of the results. CONCLUSION: A major strength of this study is the systematic and structured evaluation of a vast array of variables related to the clinical expression of OCD, including epigenetic factors and ratings derived from instruments evaluating family accommodation. The presence of sexual/religious symptoms, low economic status and high modification on family function due to OCD were independently associated with treatment-refractoriness. Future longitudinal studies are warranted to verify if these variables represent predictive factors of treatment non-response.

Adult↗
PubMed2004

The role of RNA interference in heterochromatic silencing.

Soon after its discovery 75 years ago, heterochromatin, a dense chromosomal material, was found to silence genes. But its importance in regulating gene expression was controversial. Long thought to be inert, heterochromatin is now known to give rise to small RNAs, which, by means of RNA interference, direct the modification of proteins and DNA in heterochromatic repeats and transposable elements. Heterochromatin has thus emerged as a key factor in epigenetic regulation of gene expression, chromosome behaviour and evolution.

Animals↗
PubMed2002

Selective clonal expansion and microenvironmental permissiveness in tobacco carcinogenesis.

Historically our knowledge about the direct carcinogenic activity of cigarette smoke and its constituents grew from painting experiments on the skin of mice to produce papillomas and carcinomas. The neutral fraction of cigarette smoke condensate had most of the carcinogenic activity in this test and was rich in carcinogenic polycyclic aromatic hydrocarbons (PAHs), the most abundant by far being BP. However, the concentration of BP in the condensate was only about 2% the amount of pure BP required to cause skin tumors. In other fractions there were non-carcinogenic constituents that promoted tumor formation when applied repeatedly to mouse skin that had been initiated by a single subcarcinogenic application of BP. There were also constituents of cigarette smoke that acted as co-carcinogens when applied simultaneously with repeated applications of BP. BP was effective as an initiator at lower concentrations than as a complete carcinogen, and some non-carcinogenic PAHs in the condensate were also active initiators. It was concluded from these studies that cigarette smoke condensate is primarily a tumor-promoting and co-carcinogenic agent with weak activity as a complete carcinogen. A major effect of promoters, and possibly of co-carcinogens, is a diffuse hyperplasia which includes selective expansion of clones carrying endogenous mutations and/or mutations induced by PAHs and other carcinogens such as NNK. The induced mutations as well as damaged cells would occur throughout the exposed region and, along with the hyperplasia, increase the permissiveness of the cellular microenvironment for neoplastic expression of any potential tumor cell in its midst. Since neither the promoters nor co-carcinogens in tobacco smoke are known to interact directly with DNA, their effects can be considered epigenetic processes that act upon genetically altered cells. Examples are cited from studies of experimental skin carcinogenesis, smoking-induced histopathological changes in human lung and spontaneous transformation in cell culture to illustrate the genetic and epigenetic interactions of neoplastic development in general and their significance for smoking-induced lung cancer in particular. Certain dietary modifications that appear to be effective in moderating the promotional phase of animal and human carcinogenesis are suggested for trial in managing lung cancer.

Animals↗
PubMed2001

Translating the histone code.

Chromatin, the physiological template of all eukaryotic genetic information, is subject to a diverse array of posttranslational modifications that largely impinge on histone amino termini, thereby regulating access to the underlying DNA. Distinct histone amino-terminal modifications can generate synergistic or antagonistic interaction affinities for chromatin-associated proteins, which in turn dictate dynamic transitions between transcriptionally active or transcriptionally silent chromatin states. The combinatorial nature of histone amino-terminal modifications thus reveals a "histone code" that considerably extends the information potential of the genetic code. We propose that this epigenetic marking system represents a fundamental regulatory mechanism that has an impact on most, if not all, chromatin-templated processes, with far-reaching consequences for cell fate decisions and both normal and pathological development.

Acetylation↗