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Sperm epigenetic profile and risk of cancer

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Introduction and objective. The integrity, stability and composition of sperm chromatin are of great importance in the fertilizing potential of male gametes and their capacity to support normal embryonic development. In this study, the author presents the current state of knowledge about the sperm epigenetic profile and risk of cancer. Abbreviated description of the state of knowledge. The obtaining of pregnancy and the state of health of the baby depends on the quality of the genetic material of both the female and the male. Health behaviours and environmental factors directly affect the quality of sperm, as well as the human egg cell and, consequently, on the reproductive capabilities, the course of pregnancy and the state of the newborn. There exist two thoroughly investigated epigenetic modifications: DNA methylation and histone modifications. The process of DNA methylation can be also a fundamental factor contributing to the development of cancer, where epigenotype undergoes significant modifications. When considering numerous DNA aberrations in the male gamete, the most commonly encountered is DNA fragmentation, particularly in infertile subjects. Surprisingly, an intracytoplasmatic sperm injection study of mice oocytes, using spermatozoa with a high DNA Fragmentation Index (DFI), revealed that a considerable percentage of adults born as a result of this method, showed a significant increase in the incidence of abnormal behavioural tests, malformations, cancer and signs of premature aging. Summary. The issue of assisted procreation raises the need to look for an appropriate treatment for males with sperm chromatin abnormalities. As a result, the fight against smoking addiction becomes the obvious necessity. Moreover, the reasonable solution nowadays seems to be supplementation with micronutrients and folic acid. It has been proved that the process of DNA fragmentation is a phenomenon that intensifies over time. Therefore, there should be a pursuance for, as close as possible, to the moment of ejaculation, application of semen to reproductive techniques. Finally, epigenetic changes are suspected of being one of the factors responsible for the deterioration of male sperm parameters observed in recent decades.
In angiosperms, seed development initiates after a double fertilization event in the female gametophyte, in which one male sperm cell fuses to the central cell to form the endosperm and the other to the egg cell to form the embryo. Sexually-derived seed is thus characterized by maternal and paternal contributions to the progeny. Some plant species have the capacity to form seeds asexually, a process known as apomixis. This mode of reproduction is characterized by a bypass of meiotic reduction and the absence of paternal contribution to the embryo, resulting in a seed with an embryo genetically identical to the mother. Little is known about the molecular events that regulate apomictic development. Recent findings show that the apomictic and sexual developmental programs share molecular components, suggesting that apomixis is a deregulated sexual program. Furthermore, the identification of apomictic developmental features in fertilization-independent seed (fis) mutants in the sexual model plant Arabidopsis has also shed light on the molecular events that control sexual seed development, and has opened new questions as to the molecular nature of autonomous seed development. FIS-class genes are homologues of the Polycomb Group (PcG) chromatin remodelling factors conserved in Drosophila and humans, where they have been implicated in gene repression and control of cell fate throughout development. fis phenotypes are affected by DNA methylation, a DNA alteration associated with heterochromatin formation and gene silencing. Thus, the chromatin environment can be manipulated to make certain regions of the genome more or less susceptible to transcription; this form of control, in which gene expression patterns are altered without a change in the DNA sequence itself, is defined as epigenetic regulation. Different aspects of plant development have been shown to be controlled by epigenetic regulation. This review will highlight recent advances in understanding the epigenetic control of seed development. They are discussed in light of a model whereby altered epigenetic mechanisms might lead to complete maternal control of reproductive development as seen in apomixis.
 Phosphorylation and dephosphorylation processes catalyzed by numerous kinases and phosphorylases are essential for cell homeostasis and may lead to disturbances in a variety of vital cellular pathways, such as cell proliferation and differentiation, and thus to complex diseases including cancer. As over 80 % of all oncogenes encode protein tyrosine kinases (PTKs), protein tyrosine phosphatases (PTPs), which can reverse the effects of tyrosine kinases, are very important tumor suppressors. Alterations in tyrosine kinase and phosphatase genes including point mutations, changes in epigenetic regulation, as well as chromosomal aberrations involving regions critical to these genes, are frequently observed in a variety of cancers. Colorectal cancer (CRC) is one of the most common cancers in humans. CRCs occur in a familial (about 15 % of all cases), hereditary (about 5%) and sporadic (almost 75-80 %) form. As genetic-environmental interrelations play an important role in the susceptibility to sporadic forms of CRCs, many studies are focused on genetic alterations in such tumors. Mutational analysis of the tyrosine phosphatome in CRCs has identified somatic mutations in PTPRG, PTPRT, PTPN3, PTPN13 and PTPN14. The majority of these mutations result in a loss of protein function. Also, alterations in the expression of these genes, such as decreased expression of PTPRR, PTPRO, PTPRG and PTPRD, mediated by epigenetic mechanisms have been observed in a variety of tumors. Since cancer is a social and global problem, there will be a growing number of studies on alterations in the candidate cancer genes, including protein kinases and phosphatases, to determine the origin, biology and potential pathways for targeted anticancer therapy.
There is no doubt that cancer is not only a genetic disease but that it can also occur due to epigenetic abnormalities. Diet and environmental factors can alter the scope of epigenetic regulation. The results of recent studies suggest that O-GlcNAcylation, which involves the addition of N-acetylglucosamine on the serine or threonine residues of proteins, may play a key role in the regulation of the epigenome in response to the metabolic status of the cell. Two enzymes are responsible for cyclic O-GlcNAcylation: O-GlcNAc transferase (OGT), which catalyzes the addition of the GlcNAc moiety to target proteins; and O-GlcNAcase (OGA), which removes the sugar moiety from proteins. Aberrant expression of O-GlcNAc cycling enzymes, especially OGT, has been found in all studied human cancers. OGT can link the cellular metabolic state and the epigenetic status of cancer cells by interacting with and modifying many epigenetic factors, such as HCF-1, TET, mSin3A, HDAC, and BAP1. A growing body of evidence from animal model systems also suggests an important role for OGT in polycomb-dependent repression of genes activity. Moreover, O-GlcNAcylation may be a part of the histone code: O-GlcNAc residues are found on all core histones.
Linear models based on proportionality between variables have been commonly applied in biology and medicine but in many cases they do not describe correctly the complex relationships of living organisms and now are being replaced by nonlinear theories of deterministic chaos. Recent advances in molecular biology and genome sequencing may lead to a simplistic view that all life processes in a cell, or in the whole organism, are strictly and in a linear fashion controlled by genes. In reality, the existing phenotype arises from a complex interaction of the genome and various environmental factors. Regulation of gene expression in the animal organism occurs at the level of epigenetic DNA modification, RNA transcription, mRNA translation, and many additional alterations of nascent proteins. The process of transcription is highly complicated and includes hundreds of transcription factors, enhancers and silencers, as well as various species of low molecular mass RNAs. In addition, alternative splicing or mRNA editing can generate a family of polypeptides from a single gene. Rearrangement of coding DNA sequences during somatic recombination is the source of great variability in the structure of immunoglobulins and some other proteins. The process of rearrangement of immunoglobulin genes, or such phenomena as parental imprinting of some genes, appear to occur in a random fashion. Therefore, it seems that the mechanism of genetic information flow from DNA to mature proteins does not fit the category of linear relationship based on simple reductionism or hard determinism but would be probably better described by nonlinear models, such as deterministic chaos.
In recent years it has become apparent that epigenetic events are potentially equally responsible for cancer initiation and progression as genetic abnormalities. DNA methylation is the main epigenetic modification in humans. Two DNA methylation lesions coexist in human neoplasms: hypermethylation of promoter regions of specific genes within a context of genomic hypomethylation. Aberrant methylation is found at early stages of carcinogenesis and distinct types of cancer exhibit specific patterns of methylation changes. Tumor specific DNA is readily obtainable from different clinical samples and methylation status analysis often permits sensitive disease detection. Methylation markers may also serve for prognostic and predictive purposes as they often reflect the metastatic potential and sensitivity to therapy. As current findings show a great potential of recently characterised methylation markers, more studies in the field are needed in the future. Large clinical studies of newly developed markers are especially needed. The review describes the diagnostic potential of DNA methylation markers.
Model organisms are essential to study the genetic basis of human diseases. Transgenic mammalian models, especially genetic knock-out mice have catalysed the progress in this area. To continue the advancement, further sophisticated and refined models are crucially needed to study the genetic basis and manifestations of numerous human diseases. Coinciding with the start of the new era of post-genomic research, new tools for establishment of transgenesis, such as nuclear transfer and gene targeting in somatic cells, have become available, offering a unique opportunity for the generation of transgenic animal models. The new technology provides important tools for comparative functional genomics to promote the interpretation and increase the practical value of the data generated in numerous mouse models. This paper discusses the state-of-the-art of the nuclear replacement technology and presents future perspectives.
The melanocortin-4 receptor (Mc4r) plays an important role in body-weight regulation. This study examines the methylation status and expression levels of the Mc4r gene in response to a standard and a high-fat diet in the obese Berlin fat mouse inbred (BFMI) line and the lean C57BL/6NCrl (B6) line of Mus musculus. The methylation status of CpG sites located within the Mc4r exon was analyzed by bisulfite genomic sequencing of genomic DNA of brain tissues, and gene expression analysis was performed by real-time PCR. In both lines, the methylation of CpGs 1-8 (near the transcription start) was lower than methylation of CpGs 9-16 (located towards the end of the selected amplicon). On the standard diet, the methylation status did not differ between the lines. In response to high-fat diet, methylation of the CpGs near the transcription start was decreased in both lines. The Mc4r gene expression, however, was only marginally increased in BMFI mice, whereas there was no change in B6 mice. The results suggest that a long-term high-fat diet might have an effect on the methylation status of the Mc4r gene. However, the effect of methylation on Mc4r expression seems to be a variable compensated by other regulating factors in a line-specific manner.
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