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PubMed2003

Maintenance of CpG methylation is essential for epigenetic inheritance during plant gametogenesis.

In mammals, the DNA methyltransferase 1 (Dnmt1) faithfully copies the pattern of cytosine methylation at CpG sites to the newly synthesized strand, and this is essential for epigenetic inheritance. In Arabidopsis thaliana, several DNA methyltransferases or chromatin modifiers coupled to methylation changes have been characterized, and mutations that cause loss of their function are recessive. This is surprising because plant gametogenesis includes postmeiotic DNA replication in haploid nuclei before fertilization. Therefore, the recessive character of the mutations excludes the affected components from a regulatory role in postmeiotic maintenance or modification of epigenetic states. Here we show, however, that depletion of A. thaliana MET1, a homolog of mammalian Dnmt1 (ref. 8), results in immense epigenetic diversification of gametes. This diversity seems to be a consequence of passive postmeiotic demethylation, leading to gametes with fully demethylated and hemidemethylated DNA, followed by remethylation of hemimethylated templates once MET1 is again supplied in a zygote.

Animals↗

PubMed2005

Mapping of genetic and epigenetic regulatory networks using microarrays.

The highly coordinated expression of thousands of genes in an organism is regulated by the concerted action of hundreds of transcription factors and chromatin proteins, as well as by epigenetic mechanisms. Understanding the architecture of these vastly complex regulatory networks is one of the main challenges in the postgenomic era. New microarray-based techniques have become available for the genome-wide mapping of in vivo protein-DNA interactions and epigenetic marks. Data sets obtained with these techniques begin to offer the first comprehensive views of genetic and epigenetic regulatory networks.

Animals↗

PubMed2006

Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction?

Chromatin alterations have been associated with all stages of tumour formation and progression. The best characterized are epigenetically mediated transcriptional-silencing events that are associated with increases in DNA methylation - particularly at promoter regions of genes that regulate important cell functions. Recent evidence indicates that epigenetic changes might 'addict' cancer cells to altered signal-transduction pathways during the early stages of tumour development. Dependence on these pathways for cell proliferation or survival allows them to acquire genetic mutations in the same pathways, providing the cell with selective advantages that promote tumour progression. Strategies to reverse epigenetic gene silencing might therefore be useful in cancer prevention and therapy.

Cell Proliferation↗

PubMed2006

Inherited epigenetic variation--revisiting soft inheritance.

Phenotypic variation is traditionally parsed into components that are directed by genetic and environmental variation. The line between these two components is blurred by inherited epigenetic variation, which is potentially sensitive to environmental inputs. Chromatin and DNA methylation-based mechanisms mediate a semi-independent epigenetic inheritance system at the interface between genetic control and the environment. Should the existence of inherited epigenetic variation alter our thinking about evolutionary change?

Animals↗

PubMed2002

The fundamental role of epigenetic events in cancer.

Patterns of DNA methylation and chromatin structure are profoundly altered in neoplasia and include genome-wide losses of, and regional gains in, DNA methylation. The recent explosion in our knowledge of how chromatin organization modulates gene transcription has further highlighted the importance of epigenetic mechanisms in the initiation and progression of human cancer. These epigenetic changes -- in particular, aberrant promoter hypermethylation that is associated with inappropriate gene silencing -- affect virtually every step in tumour progression. In this review, we discuss these epigenetic events and the molecular alterations that might cause them and/or underlie altered gene expression in cancer.

Chromosome Mapping↗

PubMed2024

Epigenetic signature of very low birth weight in young adult life.

BACKGROUND: Globally, one in ten babies is born preterm (<37 weeks), and 1-2% preterm at very low birth weight (VLBW, <1500 g). As adults, they are at increased risk for a plethora of health conditions, e.g., cardiometabolic disease, which may partly be mediated by epigenetic regulation. We compared blood DNA methylation between young adults born at VLBW and controls. METHODS: 157 subjects born at VLBW and 161 controls born at term, from the Helsinki Study of Very Low Birth Weight Adults, were assessed for peripheral venous blood DNA methylation levels at mean age of 22 years. Significant CpG-sites (5'-C-phosphate-G-3') were meta-analyzed against continuous birth weight in four independent cohorts (pooled n = 2235) with cohort mean ages varying from 0 to 31 years. RESULTS: In the discovery cohort, 66 CpG-sites were differentially methylated between VLBW adults and controls. Top hits were located in HIF3A, EBF4, and an intergenic region nearest to GLI2 (distance 57,533 bp). Five CpG-sites, all in proximity to GLI2, were hypermethylated in VLBW and associated with lower birth weight in the meta-analysis. CONCLUSION: We identified differentially methylated CpG-sites suggesting an epigenetic signature of preterm birth at VLBW present in adult life. IMPACT: Being born preterm at very low birth weight has major implications for later health and chronic disease risk factors. The mechanism linking preterm birth to later outcomes remains unknown. Our cohort study of 157 very low birth weight adults and 161 controls found 66 differentially methylated sites at mean age of 22 years. Our findings suggest an epigenetic mark of preterm birth present in adulthood, which opens up opportunities for mechanistic studies.

Humans↗

PubMed2026

Timing of adverse childhood experiences shapes epigenetic ageing and life-history outcomes.

Early-life adversity is widely linked to accelerated biological ageing, yet it remains unclear whether such associations reflect exposure during sensitive developmental periods, the cumulative burden of exposures, or temporal proximity to later outcomes. Here, we leverage life-history theory and a life course framework to nuance how the timing of adverse childhood experiences (ACEs) becomes biologically embedded through epigenetic ageing. Using longitudinal data from the Future of Families and Child Wellbeing Study (N=1,974), we apply statistical learning and structured life course modelling to test sensitive period, cumulative risk, and recency hypotheses across multiple domains of adversity (poverty, instability, deprivation, and maltreatment). We find that adversity exposure during specific developmental periods, rather than cumulative burden or recent exposure, are most strongly associated with epigenetic age acceleration in late childhood ([Formula: see text]=0.003). Moreover, the timing and direction of these effects vary by adversity type. Epigenetic ageing is in turn associated with later health-related risks ([Formula: see text]=0.29, SE=0.06; [Formula: see text]=1.62, SE=0.27) and demographic behaviour ([Formula: see text]=0.21, SE=0.08; [Formula: see text]=0.22, SE=0.11), and further mediates the association between ACEs and outcomes in young adulthood, particularly for BMI ([Formula: see text]=0.003, SE=0.002, [Formula: see text]=11%). These findings demonstrate that childhood adversity may be linked to biological ageing in developmentally specific and domain-dependent ways, with certain developmental periods appearing more sensitive to adversity exposure than others.

Humans↗

PubMed2005

Epigenetic alteration at the DLK1-GTL2 imprinted domain in human neoplasia: analysis of neuroblastoma, phaeochromocytoma and Wilms' tumour.

Epigenetic alterations in the 11p15.5 imprinted gene cluster are frequent in human cancers and are associated with disordered imprinting of insulin-like growth factor (IGF)2 and H19. Recently, an imprinted gene cluster at 14q32 has been defined and includes two closely linked but reciprocally imprinted genes, DLK1 and GTL2, that have similarities to IGF2 and H19, respectively. Both GTL2 and H19 are maternally expressed RNAs with no protein product and display paternal allele promoter region methylation, and DLK1 and IGF2 are both paternally expressed. To determine whether methylation alterations within the 14q32 imprinted domain occur in human tumorigenesis, we investigated the status of the GTL2 promoter differentially methylated region (DMR) in 20 neuroblastoma tumours, 20 phaeochromocytomas and, 40 Wilms' tumours. Hypermethylation of the GTL2 promoter DMR was detected in 25% of neuroblastomas, 10% of phaeochromocytoma and 2.5% of Wilms' tumours. Tumours with GTL2 promoter DMR hypermethylation also demonstrated hypermethylation at an upstream intergenic DMR thought to represent a germline imprinting control element. Analysis of neuroblastoma cell lines revealed that GTL2 DMR hypermethylation was associated with transcriptional repression of GTL2. These epigenetic findings are similar to those reported in Wilms' tumours in which H19 repression and DMR hypermethylation is associated with loss of imprinting (LOI, biallelic expression) of IGF2. However, a neuroblastoma cell line with hypermethylation of the GTL2 promoter and intergenic DMR did not show LOI of DLK1 and although treatment with a demethylating agent restored GTL2 expression and reduced DLK1 expression. As described for IGF2/H19, epigenetic changes at DLK1/GTL2 occur in human cancers. However, these changes are not associated with DLK1 LOI highlighting differences in the imprinting control mechanisms operating in the IGF2-H19 and DLK1-GTL2 domains. GTL2 promoter and intergenic DMR hypermethylation is associated with the loss of GTL2 expression and this may contribute to tumorigenesis in a subset of human cancers.

Base Sequence↗

PubMed2006

Implication of abnormal epigenetic patterns for human diseases.

Significant evidences have brought new insights on the mechanisms by which epigenetic machinery proteins regulate gene expression, leading to a redefinition of chromatin regulation in terms of modification of core histones, DNA methylation, RNA-mediated silencing pathways, action of methylation-dependent sensitive insulators and Polycomb/Trithorax group proteins. Consistent with these fundamental aspects, an increasing number of human pathologies have been found to be associated with aberrant epigenetics regulation, including cancer, mental retardation, neurodegenerative symptoms, imprinting disorders, syndromes involving chromosomal instabilities and a great number of human life-threatening diseases. The possibility of reversing epigenetic marks, in contrast to genetic code, may provide new pharmacological targets for emerging therapeutic intervention.

Chromatin Assembly and Disassembly↗

PubMed2002

Genetic and epigenetic modification of mismatch repair genes hMSH2 and hMLH1 in sporadic breast cancer with microsatellite instability.

Breast cancer is the most common cancer in women, but its pathogenesis is still unclear. Microsatellite instability (MSI) has been identified in breast cancer cells, suggesting an association with mismatch repair defects. To test this hypothesis, we investigated MSI, protein expression of hMSH2 and hMLH1, as well as genetic and epigenetic modifications of these two genes in 32 sporadic breast tumors. MSI was identified in 15 cases. Immunohistochemistry analysis revealed that all MSI cases but one had lower than normal expression of hMSH2 (nine cases), hMLH1 (12 cases), or both (seven cases). In tumors with MSI, both genetic and epigenetic modifications of these mismatch repair genes were also identified. Eight cases harbored mutations or polymorphisms in hMSH2 and hMLH1, and 10 exhibited hypermethylation in the promoter region of hMLH1. These results suggest that both genetic and epigenetic alterations of hMSH2 and especially of hMLH1 contribute to genomic instability and tumorigenesis in sporadic breast cancer.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Frequent epigenetic inactivation of the RASSF1A tumour suppressor gene in testicular tumours and distinct methylation profiles of seminoma and nonseminoma testicular germ cell tumours.

Testicular germ cell tumours (TGCTs) are histologically heterogeneous neoplasms with variable malignant potential. Previously, we demonstrated frequent 3p allele loss in TGCTs, and recently we and others have shown that the 3p21.3 RASSF1A tumour suppressor gene (TSG) is frequently inactivated by promoter hypermethylation in a wide range of cancers including lung, breast, kidney and neuroblastoma. In order to investigate the role of epigenetic events in the pathogenesis of TGCTs, we analysed the promoter methylation status of RASSF1A and nine other genes that may be epigenetically inactivated in cancer (p16(INK4A), APC, MGMT, GSTP1, DAPK, CDH1, CDH13, RARbeta and FHIT) in 24 primary TGCTs (28 histologically distinct components). RASSF1A methylation was detected in four of 10 (40%) seminomas and 15 of 18 (83%) nonseminoma TGCT (NSTGCT) components (P=0.0346). None of the other nine candidate genes were methylated in seminomas, but MGMT (44%), APC (29%) and FHIT (29%) were frequently methylated in NSTGCTs. Furthermore, in two mixed germ cell tumours, the NSTGCT component for one demonstrated RASSF1A, APC and CDH13 promoter methylation, but the seminoma component was unmethylated for all genes analysed. In the second mixed germ cell tumour, the NSTGCT component was methylated for RASSF1A and MGMT, while the seminoma component was methylated only for RASSF1A. In all, 61% NSTGCT components but no seminoma samples demonstrated promoter methylation at two or more genes (P=0.0016). These findings are consistent with a multistep model for TGCT pathogenesis in which RASSF1A methylation occurs early in tumorigenesis and additional epigenetic events characterize progression from seminoma to NSTGCTs.

Acid Anhydride Hydrolases↗

PubMed2003

Cancer epigenetics.

Aberrant DNA methylation of the promoter region is a key mechanism for inactivation of genes that suppress tumorigenesis. Genes that are involved in every step of tumor formation can be silenced by this mechanism. Inhibitors of DNA methylation, such as 5-azadeoxycytidine (5AZA), can reverse this epigenetic event suggesting a potential use in cancer therapy. The structure of chromatin can also play an important role with respect to the regulation of gene expression. Chromatin containing hypoacetylated lysines in histones has a compact structure that is repressive for transcription. Inhibitors of histone deacetylase (HDAC) can convert chromatin to an open structure and activate certain genes that inhibit tumor growth. These HDAC inhibitors also have potential in cancer therapy. A 'cross-talk' between DNA methylation and histone deacetylation can occur and work in concert to silence gene expression. The molecular mechanism involves the attachment of a methylated CpG binding protein (MBP) to the methylated promoters and its recruitment of HDAC to form a complex that suppresses transcription. These two epigenetic modifications represent an interesting target for therapeutic intervention using 5AZA and HDAC inhibitors. These agents in combination have been shown to produce a synergistic reactivation of tumor suppressor genes and an enhanced antineoplastic effect against tumor cells, and should be investigated as a novel form of epigenetic therapy for cancer.

Angiogenesis Inhibitors↗

PubMed2003

Genetic and epigenetic alterations as hallmarks of the intricate road to cancer.

Despite the clonal origin of most tumors, their tremendous heterogeneity suggests that cancer progression springs from the combined forces of both genetic and epigenetic events, which produce variant clonal populations, together with the selective pressures of the microenvironment, which promote growth and, perhaps, dissemination of variants with a specific set of characteristics. Although the importance of genetic mutations in cancer has long been recognized, the role of epigenetic events has been suggested more recently. This review focuses on the genetic and epigenetic molecular mechanisms involved in cancer onset and progression, and discusses the possibility of new strategies in the development of anticancer treatments.

Cell Cycle↗

PubMed2003

Epigenetic targets for immune intervention in human malignancies.

Emerging evidences suggest that epigenetic events associated with tumor development and progression, such as deregulated methylation of CpG dinucleotides and aberrant histone acetylation, may impair the immunogenic potential of cancer cells. In fact, DNA hypermethylation and/or histone deacetylation contribute to the absent or downregulated expression of different components of the 'tumor recognition complex' (i.e., HLA class I antigens, cancer/testis antigens and accessory/costimulatory molecules) in solid and hemopoietic human malignancies. However, pharmacologic agents that induce DNA hypomethylation or inhibit histone deacetylation can modify these epigenetic phenomena, restoring the defective expression of selected components of the 'tumor recognition complex' in cancer cells. These antigenic modifications positively modulate the immunogenicity and the immune recognition of cancer cells, making epigenetic drugs attractive agents to design new combined chemoimmunotherapeutic strategies for the treatment of cancer patients.

Antigens, Neoplasm↗

PubMed2005

Tumor-specific exon 1 mutations could be the 'hit event' predisposing Rb2/p130 gene to epigenetic silencing in lung cancer.

Genetic alterations in Rb2/p130 gene have been reported in several tumors, but till now there are insufficient and conflicting data linking the loss of pRb2/p130 expression with the mutational status of this gene in lung cancer. We recently reported that loss or lowering of pRb2/p130 expression is mainly due to aberrant Rb2/p130 promoter methylation, in retinoblastoma tumors, and indicated that epigenetic silencing of Rb2/p130 can impair its function to negatively regulate cell cycle progression as well as apoptotic response. In order to clarify Rb2/p130 gene inactivation in lung cancer, we investigated whether epigenetic events could impair the expression of this gene in NSLC. Here, we show that specific Rb2-exon 1 homozygous mutations, occurring in an Rb2/p130, region, rich in CpG dinucleotides, could be the 'hit event' that predispose this gene to epigenetic changes, leading to Rb2/p130 gene silencing in lung cancer. Moreover, these homozygous mutations, found in different tumor histotypes, could represent tumor-specific markers.

Base Sequence↗

PubMed2006

RAR-mediated epigenetic control of the cytochrome P450 Cyp26a1 in embryocarcinoma cells.

Retinoic acid (RA) is a signaling molecule that plays a pivotal role in major cellular processes and vertebrate development. RA action is mediated by specialized transcription factors, the nuclear RA receptors (RARs), which regulate the transcription of genes containing a RA-responsive element (RARE). Here we demonstrate that the genes for the RA-receptor RARbeta2 and the cytochrome P450 RA-specific hydrolase Cyp26a1 involved in RA catabolism are coordinately regulated by RA. We found that both RARbeta2 and Cyp26a1 genes are epigenetically silenced in the absence of DNA methylation in RAC65, a P19 embryocarcinoma cell line derivative carrying a dominant-negative RARalpha mutant and resistant to the growth-inhibitory and differentiation effects of RA. In response to RA, RARbeta2 transcription is epigenetically regulated by RARalpha. Similarly, we found that Cyp26a1 transcription is epigenetically regulated by RARbeta2. Knocking down RARbeta2 transcription by RNA interference in wild-type P19 cells, with an intact RARalpha, induced Cyp26a1 transcriptional repression in the absence of DNA methylation. Concomitantly, cells developed RA resistance and did not undergo RA-induced neuron differentiation. Apparently, RARalpha, RARbeta2 and Cyp26a1 are components of a RA-regulated gene network. Factors affecting an upstream gene of the network can trigger repressive chromatin changes -- which are propagated in a domino fashion - at downstream genes of the network. This study also shows that chromatin inactivity, and consequent transcriptional silencing, can be achieved in the absence of DNA methylation.

Animals↗

PubMed2006

Epigenetics and the plasticity of differentiation in normal and cancer stem cells.

Embryonic stem cells are characterized by their differentiation to all cell types during embryogenesis. In adult life, different tissues also have somatic stem cells, called adult stem cells, which in specific niches can undergo multipotent differentiation. The use of these adult stem cells has considerable therapeutic potential for the regeneration of damaged tissues. In both embryonic and adult stem cells, differentiation is controlled by epigenetic mechanisms, and the plasticity of differentiation in these cells is associated with transcription accessibility for genes expressed in different normal tissues. Abnormalities in genetic and/or epigenetic controls can lead to development of cancer, which is maintained by self-renewing cancer stem cells. Although the genetic abnormalities produce defects in growth and differentiation in cancer stem cells, these cells have not always lost the ability to undergo differentiation through epigenetic changes that by-pass the genomic abnormalities, thus creating the basis for differentiation therapy. Like normal stem cells, cancer stem cells can show plasticity for differentiation. This plasticity of cancer stem cells is also associated with transcription accessibility for genes that are normally expressed in different tissues, including tissues other than those from which the cancers originated. This broad transcription accessibility can also contribute to the behavior of cancer cells by overexpressing genes that promote cell viability, growth and metastasis.

Adult Stem Cells↗

PubMed2001

The marks, mechanisms and memory of epigenetic states in mammals.

It is well recognized that there is a surprising degree of phenotypic variation among genetically identical individuals, even when the environmental influences, in the strict sense of the word, are identical. Genetic textbooks acknowledge this fact and use different terms, such as 'intangible variation' or 'developmental noise', to describe it. We believe that this intangible variation results from the stochastic establishment of epigenetic modifications to the DNA nucleotide sequence. These modifications, which may involve cytosine methylation and chromatin remodelling, result in alterations in gene expression which, in turn, affects the phenotype of the organism. Recent evidence, from our work and that of others in mice, suggests that these epigenetic modifications, which in the past were thought to be cleared and reset on passage through the germline, may sometimes be inherited to the next generation. This is termed epigenetic inheritance, and while this process has been well recognized in plants, the recent findings in mice force us to consider the implications of this type of inheritance in mammals. At this stage we do not know how extensive this phenomenon is in humans, but it may well turn out to be the explanation for some diseases which appear to be sporadic or show only weak genetic linkage.

Agouti Signaling Protein↗