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PubMed2004

DNA methylation and male infertility.

Male infertility is one of the biggest concerns of today's health care community. In the US and other developed countries, approximately 70% of infertility among couples is attributed to male reproductive failure. Alterations in reproductive organ development and sperm production have been listed as the major causes of this phenomenon. Sex determination and differentiation, X chromosome inactivation, gene imprinting and normal germ cell development are important biological processes that, in turn, control mammalian reproduction. Specific patterns of gene expression and repression are important in such processes. The strong correlation between DNA methylation, a major epigenetic modification of the genome, and gene expression patterns is well documented. The effects of DNA methylation on the expression of genes affecting male reproductive organ development, spermatogenesis, and male sexual behavior have been reported, suggesting that alterations in DNA methylation could induce abnormal male sexual development and reproductive performance. Inheritance of epigenetic processes and changes in DNA methylation patterns induced by certain diets have been demonstrated in recent years. However, the effects of DNA methylation on male fertility have not been well studied. Since inherited altered DNA methylation patterns could be a cause of increased susceptibility to xenobiotics or abnormal phenotype in future generations, multigenerational studies oriented to determine the effects of xenobiotics affecting DNA methylation in male fertility are recommended.

DNA Methylation↗
PubMed2025

Sex-Chromosome-Dependent Ageing in Female Heterogametic Methylomes.

Recent research in humans and both model and non-model animals has shown that DNA methylation (DNAm), an epigenetic modification, is one of the mechanisms underlying the ageing process. DNAm-based indices predict mortality and provide valuable insights into biological ageing mechanisms. Although sex-dependent differences in lifespan are ubiquitous and sex chromosomes are thought to play an important role in sex-specific ageing, they have been largely ignored in epigenetic ageing studies. We characterised the genome-wide distribution of age-related CpG (Cytosine-phosphate-Guanine) sites from longitudinal samples in two avian species (zebra finch and jackdaw), including for the first time the avian sex chromosomes (Z and the female-specific, haploid W). In both species, we find a small fraction of the CpG sites to show age-related changes in DNAm with the majority of them being located on the haploid, female-specific W chromosome, where DNAm levels predominantly decrease with age. Age-related CpG sites were over-represented on the zebra finch but under-represented on the jackdaw Z chromosome. Our results highlight distinct age-related changes in sex chromosome DNAm compared to the rest of the genome in two avian species, suggesting this previously understudied feature of sex chromosomes may be instrumental in sex-dependent ageing. Moreover, studying the DNAm of sex chromosomes might be particularly useful in ageing research, facilitating the identification of shared (sex-dependent) age-related pathways and processes between phylogenetically diverse organisms.

Animals↗
PubMed2005

Epigenetic status of the H19 locus in human oocytes following in vitro maturation.

Imprinting is an epigenetic modification that is reprogrammed in the germ line and leads to the monoallelic expression of some genes. Imprinting involves DNA methylation. Maternal imprint is reset during oocyte growth and maturation. In vitro maturation (IVM) of oocytes may, therefore, interfere with imprint acquisition and/or maintenance. To evaluate if maturing human oocytes in vitro would be hazardous at the epigenetic level, we first determined the methylation profile of the H19 differentially methylated region (DMR). The methylation status of the H19 DMR seems particularly vulnerable to in vitro culture conditions. We analyzed oocytes at different stages of maturation following IVM, germinal vesicle (GV), metaphase I (MI), and metaphase II (MII), using the bisulfite mutagenesis technique. Our results indicated that the unmethylated specific maternal profile for the H19 DMR was stably established at the GV stage. The majority of MI-arrested oocytes exhibited an altered pattern of methylation, the CTCF-binding site being methylated in half of the DNA strands analyzed. Of the 20 MII oocytes analyzed, 15 showed the normal unmethylated maternal pattern, while 5 originating from two different patients exhibited a methylated pattern. These findings highlight the need for extended analysis on MII-rescued oocytes to appreciate the epigenetic safety of the IVM procedure, before it becomes a routine and practical assisted reproductive procedure.

Adult↗
PubMed2001

Imprinting and the epigenetic asymmetry between parental genomes.

Genomic imprinting confers a developmental asymmetry on the parental genomes, through epigenetic modifications in the germ line and embryo. These heritable modifications regulate the monoallelic activity of parental alleles resulting in their functional differences during development. Specific cis-acting regulatory elements associated with imprinted genes carry modifications involving chromatin structural changes and DNA methylation. Some of these modifications are initiated in the germ line. Comparative genomic analysis at imprinted domains is emerging as a powerful tool for the identification of conserved elements amenable to more detailed functional analysis, and for providing insight into the emergence of imprinting during the evolution of mammalian species. Genomic imprinting therefore provides a model system for the analysis of the epigenetic control of genome function.

Alleles↗
PubMed2003

DNA methylation, smooth muscle cells, and atherogenesis.

DNA methylation is a form of epigenetic modification of the genome that can regulate gene expression. Hypermethylation of CpG islands in the promoter areas leads to decreased gene expression, whereas promoters of actively transcribed genes remain nonmethylated. Because of cellular proliferation and monoclonality of at least some of the lesion cells, atherosclerotic lesions have been compared with benign vascular tumors.1,2 However, although genetic and epigenetic background favors neoplastic transformation, atherosclerotic plaques never develop to malignant tumors. Among cancer cells, common features are genome-wide hypomethylation, which correlates with transformation and tumor progression. Recent studies have shown that DNA methylation changes occur also during atherogenesis and may contribute to the lesion development.

Arteriosclerosis↗
PubMed2004

Beyond genetics--the emerging role of epigenetic changes in hematopoietic malignancies.

The term epigenetic refers to a heritable change in gene expression that is mediated by mechanisms other than alterations in the primary nucleotide sequence. DNA methylation at cytosine bases that are located 5' to guanosine within a CpG dinucleotide is the main epigenetic modification in humans. Patterns of DNA methylation are profoundly deranged in human cancer and comprise genome-wide losses as well as regional gains in DNA methylation. Hypermethylation of CpG islands within gene promoter regions is associated with transcriptional inactivation and represents, in addition to genetic aberrations, an important mechanism of gene silencing in the pathogenesis of hematopoietic malignancies. This epigenetic phenomenon acts as an alternative to mutations and deletions to disrupt tumor suppressor gene function. A large number of genes involving fundamental cellular pathways may be affected in virtually all types of human cancer by aberrant CpG island methylation in association with transcriptional silencing. Altered methylation patterns can be used as biomarkers for cancer detection, assessment of prognosis, and prediction of response to antitumor treatment. Furthermore, clinical trials using epigenetically targeted therapies have yielded promising results for acute and chronic leukemias as well as for myelodysplastic syndromes. The exploration of our growing knowledge about epigenetic aberrations may help develop novel strategies for the diagnosis and treatment of hematopoietic malignancies in the future.

DNA Methylation↗
PubMed2003

Profiling aberrant DNA methylation in hematologic neoplasms: a view from the tip of the iceberg.

Cancer is also an epigenetic disease. The main epigenetic modification in humans is DNA methylation. Transformed cells undergo a dramatic change in their DNA methylation patterns: certain CpG islands located in the promoter regions of tumor-suppressor genes become hypermethylated and the contiguous gene rests silenced and this phenomenon occurs in an overall genomic environment of DNA hypomethylation. The profile of CpG island hypermethylation in hematologic malignancies is an epigenetic signature unique for each subtype of leukemia or lymphoma. Although the most widely studied genes are the cell-cycle inhibitors p15INK4b and p16INK4a (specially in AML and ALL), the list of methylation-repressed genes in these neoplasms is expanding very rapidly, including MGMT, RARB2, CRBP1, SOCS-1, CDH1, DAPK1, and others. A necessary cross-talk between genetic alterations and DNA methylation exists: certain chromosomal translocations may induce hypermethylation, such as the PML-RARa, or attract methylation, such as BCR-ABL, but DNA hypomethylation can be the culprit behind the genesis of certain abnormal recombination events. From a translational standpoint, hypermethylation can be used as a marker of recurrent disease or progression, for example, in MDS, or response to chemotherapy, such as MGMT methylation in B-cell non-Hodgkin's lymphoma. Furthermore, promising studies using DNA demethylating agents and histone deacetylase inhibitors are underway to awake these dormant tumor-suppressor genes for a better treatment of the patient with a hematologic malignancy.

CpG Islands↗
PubMed2006

DNA methylation as a regulatory mechanism for gene expression in mammals.

Epigenetics refers to the study of heritable changes in gene expression that occur without a change in DNA sequence. In the last decade, it has been shown that epigenetic mechanisms provide an "extra" layer of transcriptional control that regulates genes expression. Three distinct mechanisms appear intricately related in initiating and sustaining epigenetic modifications: RNA-associated silencing, DNA methylation and histone modification. These mechanisms are critical components in the normal development and cell growth. DNA methylation is involved in transcriptional silencing of genes, regulation of expression of imprinted genes, a number of tumour suppressor genes in cancer and silencing of genes located on the inactive X chromosome. In this review, we are focused on the basic principles of DNA methylation as the main epigenetic mechanism for normal embryonic development and epigenetic alterations that contribute to carcinogenesis.

Animals↗
PubMed2002

Promoter hypermethylation of the death-associated protein kinase gene in breast cancer is associated with the invasive lobular subtype.

Expression of death-associated protein (DAP) kinase, a proapoptotic serine/threonine protein kinase, is frequently lost in human tumors. In a study of 134 primary breast cancer specimens hypermethylation of the DAP kinase gene was found in 13% of cases. A highly significant difference (P < 0.001) of DAP kinase inactivation was observed between invasive lobular cancer (n = 19) and invasive ductal cancer (n = 85; 53% versus 9%, respectively). Hypermethylation correlated with loss of RNA expression, estrogen receptor positivity (P < 0.01), and the absence of p53 overexpression (P < 0.01). In contrast to invasive lobular cancer, the in situ-growing precursor lesion lacked epigenetic modification of the DAP kinase promotor by aberrant methylation indicating a potential role in tumor progression. Unlike the DAP kinase gene, hypermethylation of the cyclin D2 and RASSF1A genes did not correlate with a particular histological subtype or to invasiveness [corrected]. We conclude that different histological subtypes of breast cancer may not only differ concerning specific chromosomal abnormalities and DNA mutations but also with regard to epigenetic inactivation patterns.

Apoptosis Regulatory Proteins↗
PubMed2006

Techniques used in studies of age-related DNA methylation changes.

Epigenetic modification of CpG islands (CGIs) in promoter regions is an important regulatory mechanism of gene expression in eukaryotic cells. Hypermethylation of CGIs may silence a gene, whereas hypomethylation of previously methylated CGIs allows gene expression. The pattern of methylation is cell-type-specific and established during development of the organisms. Changes in the methylation pattern have been found in all cancer forms and in aging cells. The epigenetic-related alternations of gene expression status may significantly contribute to the initiation and maintenance of malignant growth. Cancer incidence increases dramatically with age and correlates strongly with age-related methylation changes. Many techniques have been developed to analyze the genome-wide methylation content and the methylation status of specific loci. The majority of methylation screening protocols utilizes methylation-sensitive endonuclease digestion or bisulfite treatment of the template followed by subsequent PCR amplification of a specific sequence. All methods either examine only one specific DNA sequence at a time, or provide limited genomic information on the screened sequences. The principle of our new approach is to combine methylation-sensitive enzyme digestion with the comparative genomic hybridization (CGH) technique to develop an array-based method to screen the entire genome for changes of methylation pattern. The new technique will serve as an efficient tool in understanding the nature of epigenetic changes and their significance to the aging process and cancer development.

CpG Islands↗
PubMed2002

DNA methylation: an epigenetic pathway to cancer and a promising target for anticancer therapy.

The unique properties of a cancer cell are acquired through a stepwise accumulation of heritable changes in the information content of proto-oncogenes and tumor suppressor genes. While gain, loss, and mutation of genetic information have long been known to contribute to tumorigenesis, it has been increasingly recognized over the past 5 years that 'epigenetic' mechanisms may play an equally important role. The main epigenetic modification of the human genome is methylation of cytosine residues within the context of the CpG dinucleotide. De novo methylation of 'CpG islands' in the promoter regions of tumor suppressor genes may lead to transcriptional silencing through a complex process involving histone deacetylation and chromatin condensation, and thus represents a tumorigenic event that is functionally equivalent to genetic changes like mutation and deletion. DNA methylation is interesting from a diagnostic viewpoint because it may be easily detected in DNA released from neoplastic and preneoplastic lesions into serum, urine or sputum, and from a therapeutic viewpoint because epigenetically silenced genes may be reactivated by inhibitors of DNA methylation and/or histone deacetylase. A better understanding of epigenetic mechanisms leading to tumor formation and chemoresistance may eventually improve current cancer treatment regimens and be instructive for a more rational use of anticancer agents.

Antineoplastic Agents↗
PubMed2001

Epigenetic silencing of PEG3 gene expression in human glioma cell lines.

Genomic imprinting, the phenomenon in which alleles of genes are expressed differentially depending on their parental origins, has important consequences for mammalian development, and disturbance of normal imprinting leads to abnormal embryogenesis and some inherited diseases and is also associated with various cancers. In the context of screening for novel imprinted genes on human chromosome 19q13.4 with mouse A9 hybrids, we identified a maternal allele-specific methylated CpG island in exon 1 of paternally expressed imprinted gene 3 (PEG3), a gene that exhibits paternal allele-specific expression. Because PEG3 expression is downregulated in some gliomas and glioma cell lines, despite high-level expression in normal brain tissues, we investigated whether the loss of PEG3 expression is related to epigenetic modifications involving DNA methylation. We found monoallelic expression of PEG3 in all normal brain tissues examined and five of nine glioma cell lines that had both unmethylated and methylated alleles; the remaining four glioma cell lines exhibited gain of imprinting with hypermethylated alleles. In addition, treatment of glioma cell lines with the DNA demethylating agent 5-aza-2'-deoxycytidine reversed the silencing of PEG3 biallelically. In this article, we report that the epigenetic silencing of PEG3 expression in glioma cell lines depends on aberrant DNA methylation of an exonic CpG island, suggesting that PEG3 contributes to glioma carcinogenesis in certain cases.

Animals↗
PubMed2002

DNA methylation and chromatin - unraveling the tangled web.

Methylation of cytosines within the CpG dinucleotide by DNA methyltransferases is involved in regulating transcription and chromatin structure, controlling the spread of parasitic elements, maintaining genome stability in the face of vast amounts of repetitive DNA, and X chromosome inactivation. Cellular DNA methylation is highly compartmentalized over the mammalian genome and this compartmentalization is essential for embryonic development. When the complicated mechanisms that control which DNA sequences become methylated go awry, a number of inherited genetic diseases and cancer may result. Much new information has recently come to light regarding how cellular DNA methylation patterns may be established during development and maintained in somatic cells. Emerging evidence indicates that various chromatin states such as histone modifications (acetylation and methylation) and nucleosome positioning (modulated by ATP-dependent chromatin remodeling machines) determine DNA methylation patterning. Additionally, various regulatory factors interacting with the DNA methyltransferases may direct them to specific DNA sequences, regulate their enzymatic activity, and allow their use as transcriptional repressors. Continued studies of the connections between DNA methylation and chromatin structure and the DNA methyltransferase-associated proteins, will likely reveal that many, if not all, epigenetic modifications of the genome are directly connected. Such studies should also yield new insights into treating diseases involving aberrant DNA methylation.

Acetylation↗
PubMed2026

Gene regulatory mechanisms downstream of DNA methylation.

Cytosine DNA methylation is a conserved epigenetic modification that regulates gene expression, represses transposable elements and maintains genome stability across diverse eukaryotes. Although major advances have uncovered the pathways involved in the establishment, maintenance and removal of DNA methylation, the downstream mechanisms by which this mark influences transcriptional programmes and shapes chromatin structure are less well understood. Here, we review how specialized reader proteins and transcription factors interpret DNA methylation to preserve methylation patterns, recruit effector complexes, regulate chromatin accessibility and interact with parallel epigenetic systems to mediate transcriptional silencing and activation across mammals and plants. We highlight that robust transcriptional and epigenetic states emerge from overlapping, layered and partially redundant DNA methylation-dependent mechanisms. Together, these insights provide a framework for understanding how DNA methylation shapes the epigenome to regulate development, differentiation and disease progression.

Journal Article↗
PubMed2024

The effect of low birth weight as an intrauterine exposure on the early onset of sarcopenia through possible molecular pathways.

Sarcopenia, a musculoskeletal disease characterized by the progressive loss of skeletal muscle mass, strength, and physical performance, presents significant challenges to global public health due to its adverse effects on mobility, morbidity, mortality, and healthcare costs. This comprehensive review explores the intricate connections between sarcopenia and low birth weight (LBW), emphasizing the developmental origins of health and disease (DOHaD) hypothesis, inflammatory processes (inflammaging), mitochondrial dysfunction, circadian rhythm disruptions, epigenetic mechanisms, and genetic variations revealed through genome-wide studies (GWAS). A systematic search strategy was developed using PubMed to identify relevant English-language publications on sarcopenia, LBW, DOHaD, inflammaging, mitochondrial dysfunction, circadian disruption, epigenetic mechanisms, and GWAS. The publications consist of 46.2% reviews, 21.2% cohort studies, 4.8% systematic reviews, 1.9% cross-sectional studies, 13.4% animal studies, 4.8% genome-wide studies, 5.8% epigenome-wide studies, and 1.9% book chapters. The review identified key factors contributing to sarcopenia development, including the DOHaD hypothesis, LBW impact on muscle mass, inflammaging, mitochondrial dysfunction, the influence of clock genes, the role of epigenetic mechanisms, and genetic variations revealed through GWAS. The DOHaD theory suggests that LBW induces epigenetic alterations during foetal development, impacting long-term health outcomes, including the early onset of sarcopenia. LBW correlates with reduced muscle mass, grip strength, and lean body mass in adulthood, increasing the risk of sarcopenia. Chronic inflammation (inflammaging) and mitochondrial dysfunction contribute to sarcopenia, with LBW linked to increased oxidative stress and dysfunction. Disrupted circadian rhythms, regulated by genes such as BMAL1 and CLOCK, are associated with both LBW and sarcopenia, impacting lipid metabolism, muscle mass, and the ageing process. Early-life exposures, including LBW, induce epigenetic modifications like DNA methylation (DNAm) and histone changes, playing a pivotal role in sarcopenia development. Genome-wide studies have identified candidate genes and variants associated with lean body mass, muscle weakness, and sarcopenia, providing insights into genetic factors contributing to the disorder. LBW emerges as a potential early predictor of sarcopenia development, reflecting the impact of intrauterine exposures on long-term health outcomes. Understanding the complex interplay between LBW with inflammaging, mitochondrial dysfunction, circadian disruption, and epigenetic factors is essential for elucidating the pathogenesis of sarcopenia and developing targeted interventions. Future research on GWAS and the underlying mechanisms of LBW-associated sarcopenia is warranted to inform preventive strategies and improve public health outcomes.

Humans↗
PubMed2001

Epigenetic regulation of the KAI1 metastasis suppressor gene in human prostate cancer cell lines.

Expression of the KAI1 gene, a metastasis-suppressor for prostate cancer, is reduced in all foci of prostatic metastasis. The altered regulatory mechanism is not strongly related to mutations or allelic losses of the KAI1 gene in prostate tumors. Since transcriptional silencing of genes has been found to be caused by epigenetic mechanisms, we have investigated the involvement of this epigenetic regulation of KAI1 expression in prostate cancers. The methylation status of the KAI1 promoter region was examined by restriction-enzyme digestion and sequencing, after amplifying a 331-bp fragment in the GC-rich promoter region from 4 human prostate cancer cell lines treated with bisulfite. The same 4 cell lines were also exposed to various concentrations of the demethylating agent, 5-aza-2'-deoxycytidine (5-AzaC) and / or the histone deacetylase inhibitor, trichostatin A (TSA). To clarify the influence of epigenetic modification on reduced KAI1 mRNA expression in the tumor cells, RT-PCR and northern-blot analyses were performed. Bisulfite-sequencing data showed a few methylated CpG islands in the promoter. RT-PCR analysis of 5-AzaC and / or TSA-treated cells indicated reversal of suppression of KAI1 transcription in two cell lines (PC-3 and DU-145), although the expression could not be detected by northern blots. From these results, it is suggested that epigenetic change is not the main mechanism of KAI1 down-regulation, though there remains a possibility that methylation in a more upstream region might be associated with this regulation.

Adenocarcinoma↗
PubMed2025

Chromatin assembly by the histone chaperone HIRA facilitates Human Papillomavirus replication.

The circular, double-stranded DNA genomes of Human papillomaviruses (HPV) exist in a nucleosomal state throughout the infectious cycle and rely on host histone epigenetic modifications and chromatin assembly processes to promote various phases of the viral life cycle. Here, we show that the histone H3.3 chaperone HIRA and its associated complex members are recruited to HPV replication factories during the late phase of the HPV life cycle. HIRA is also recruited to HPV replication factories generated by amplification of a replicon with a minimal origin and expression of the viral replication proteins E1 and E2, demonstrating that the E1 and E2 proteins are sufficient for HIRA recruitment. Downregulation of HIRA expression reduces HPV31 DNA amplification and viral transcription in differentiated keratinocytes. Histone H3.3 that is highly phosphorylated on serine residue 31 is also enriched at sites of HPV replication and this modification links the DNA damage response to chromatin that supports rapid gene activation. We propose that deposition of histone H3.3 generates viral minichromosomes that are highly primed to support the late stages of the HPV life cycle.

H3.3 phosphorylation↗
PubMed1997

Genomic structure and parent-of-origin-specific methylation of Peg1.

We previously identified Peg1/Mest as a novel paternally expressed gene in the developing mouse embryo. The human PEG1 gene was recently assigned to 7q32 and shown to be imprinted and paternally expressed. Therefore, PEG1 deficiency could participate in the aetiology of pre- and post-natal growth retardation associated with maternal uniparental disomy 7 in humans. We have now initiated the characterization of the Peg1 locus in order to identify and dissect cis-acting elements implicated in its imprinted monoallelic expression. The genomic structure of Peg1 as well as the DNA sequence of the 5'-end of the gene, including 2.4 kb of promoter sequences and covering the first 2 exons, have been determined. Important sequence elements, such as a CpG island spanning exon 1 and direct repeats, are identified and discussed. To address the role of epigenetic modifications in the imprinting of Peg1, a methylation analysis of the Peg1 gene is presented. Partially methylated cytosine residues in 13.5 d.p.c. embryos and undifferentiated ES cells were identified. Using embryos carrying a targetted mutation at the Peg1 locus, we show that this partial promoter methylation pattern reflects a strict parent-of-origin-specific differential methylation: the expressed paternal allele is unmethylated, whereas the silenced maternal allele is fully methylated at the CpG sites studied. That the gametes carry the epigenetic information necessary to lay down this allele-specific methylation pattern is suggested by analysis of DNA isolated from sperm and parthenogenetic embryos.

Animals↗