Maternal and paternal factors influence offspring development and program its genome for successful postnatal life. Based on the stressors during gestation, the pregnant female prepares the fetus for the outside environment. This preparation is achieved by changing the epigenome of the fetus and is referred to as 'developmental programming'. For instance, nutritional insufficiency in utero will lead to programming events that prepare the fetus to cope up with nutrient scarcity following birth; however, offspring may not face nutrient scarcity following birth. This discrepancy between predicted and exposed postnatal environments are perceived as 'stress' by the offspring and may result in cardiovascular and metabolic disorders. Thus, this developmental programming may be both beneficial as well as harmful depending on the prenatal vs postnatal environment. Over the past three decades, accumulating evidence supports the hypothesis of Developmental Origin of Health and Disease (DOHaD) by the programming of the fetal phenotype without altering the genotype per se. These heritable modifications in gene expression occur through DNA methylation, histone modification and noncoding RNA-associated gene activation or silencing, and all are defined as epigenetic modifications. In the present review, we will summarize the evidence supporting epigenetic regulation as a significant component in DOHaD.

/pdf/epigenetic-responses-and-the-developmental-origins-of-health-5a7s5nwrf2.pdf

Epigenetic responses and the developmental origins of health and disease.

DNA methylation is an important epigenetic modification as a hallmark in cancer. Conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) by ten-eleven translocation (TET) family enzymes plays an important biological role in embryonic stem cells, development, aging and disease. Lymphoid specific helicase (LSH), a chromatin remodeling factor, is regarded as a reader of 5-hmC. Recent reports show that the level of 5-hmC is altered in various types of cancers. However, the change in 5-hmC levels in cancer and associated metastasis is not well defined. We report that the level of 5-hmC was decreased in metastatic tissues of nasopharyngeal carcinoma, breast cancer, and colon cancer relative to that in non-metastasis tumor tissues. Furthermore, our data show that TET2, but not TET3, interacted with LSH, whereas LSH increased TET2 expression through silencing miR-26b-5p and miR-29c-5p. Finally, LSH promoted genome stability by silencing satellite expression by affecting 5-hmC levels in pericentromeric satellite repeats, and LSH was resistant to cisplatin-induced DNA damage. Our data indicate that 5-hmC might serve as a metastasis marker for cancer and that the decreased expression of LSH is likely one of the mechanisms of genome instability underlying 5-hmC loss in cancer.

Decrease in Lymphoid Specific Helicase and 5-hydroxymethylcytosine Is Associated with Metastasis and Genome Instability.

DNA methyltransferases are responsible for catalyzing the methylation of adenine/cytosine residues in specific regions of the genome, and they participate in the establishment of epigenetic modification patterns. Deregulation of DNA methyltransferase activity will disturb DNA methylation systems, leading to the occurrence of various human diseases including cancers. Moreover, DNA methyltransferases may serve as promising therapeutic targets, and DNA methyltransferase inhibitors have been used for disease treatment. Therefore, the detection of DNA methyltransferases and screening of their inhibitors are crucial for both fundamental biomedical research studies and clinical practice. Due to their excellent size-dependent optical, chemical, electronic, and mechanical features, nanomaterials have been widely used as powerful building materials to construct efficient biosensors for DNA methyltransferase assay with high sensitivity and good selectivity. In this review, we summarize the recent progress in the development of nanomaterial-based biosensors for DNA methyltransferase assay including the strategies, features and applications, and highlight the future direction and challenges in this area as well.

Nanomaterial-based biosensors for DNA methyltransferase assay.

The modulation of the activity of DNA methyltransferases (DNMTs) represents a crucial epigenetic mechanism affecting gene expressions or DNA repair mechanisms in the cells. Aberrant modifications in the function of DNMTs are a fundamental event and part of the pathogenesis of human cancer. Phytochemicals, which are biosynthesized in plants in the form of secondary metabolites, represent an important source of biomolecules with pleiotropic effects and thus provide a wide range of possible clinical applications. It is well documented that phytochemicals demonstrate significant anticancer properties, and in this regard, rapid development within preclinical research is encouraging. Phytochemicals affect several epigenetic molecular mechanisms, including DNA methylation patterns such as the hypermethylation of tumor-suppressor genes and the global hypomethylation of oncogenes, that are specific cellular signs of cancer development and progression. This review will focus on the latest achievements in using plant-derived compounds and plant-based diets targeting epigenetic regulators and modulators of gene transcription in preclinical and clinical research in order to generate novel anticancer drugs as sensitizers for conventional therapy or compounds suitable for the chemoprevention clinical setting in at-risk individuals. In conclusion, indisputable anticancer activities of dietary phytochemicals linked with proper regulation of DNA methylation status have been described. However, precisely designed and well-controlled clinical studies are needed to confirm their beneficial epigenetic effects after long-term consumption in humans.

/pdf/dna-methylation-status-in-cancer-disease-modulations-by-4iyfxb56ly.pdf

DNA Methylation Status in Cancer Disease: Modulations by Plant-Derived Natural Compounds and Dietary Interventions.

Colorectal carcinogenesis (CRC) is caused by the gradual long-term accumulation of both genetic and epigenetic changes. Recently, epigenetic alterations have been included in the classification of the CRC molecular subtype, and this points out their prognostic impact. As epigenetic modifications are reversible, they may represent relevant therapeutic targets. DNA methylation, catalyzed by DNA methyltransferases (DNMTs), regulates gene expression. For many years, the deregulation of DNA methylation has been considered to play a substantial part in CRC etiology and evolution. Despite considerable advances in CRC treatment, patient therapy response persists as limited, and their profit from systemic therapies are often hampered by the introduction of chemoresistance. In addition, inter-individual changes in therapy response in CRC patients can arise from their specific (epi)genetic compositions. In this review article, we summarize the options of CRC treatment based on DNA methylation status for their predictive value. This review also includes the therapy outcomes based on the patient's methylation status in CRC patients. In addition, the current challenge of research is to develop therapeutic inhibitors of DNMT. Based on the essential role of DNA methylation in CRC development, the application of DNMT inhibitors was recently proposed for the treatment of CRC patients, especially in patients with DNA hypermethylation.

https://www.mdpi.com/2073-4409/9/6/1540/pdf

Methylation-Based Therapies for Colorectal Cancer.

DNA methyltransferases (MTases), a family of enzymes that catalyse the methylation of DNA, have a profound effect on gene regulation. A large body of evidence has indicated that DNA MTase is potentially a predictive biomarker closely associated with genetic disorders and genetic diseases like cancer. Given the attention bestowed onto DNA MTases in molecular biology and medicine, highly sensitive detection of DNA MTase activity is essential in determining gene regulation, epigenetic modification, clinical diagnosis and therapeutics. Conventional techniques such as isotope labelling are effective, but they often require laborious sample preparation, isotope labelling, sophisticated equipment and large amounts of DNA, rendering them unsuitable for uses at point-of-care. Simple, portable, highly sensitive and low-cost assays are urgently needed for DNA MTase activity screening. In most recent technological advances, many alternative DNA MTase activity assays such as fluorescent, electrochemical, colorimetric and chemiluminescent assays have been proposed. In addition, many of them are coupled with nanomaterials and/or enzymes to significantly enhance their sensitivity. Herein we review the progress in the development of DNA MTase activity assays with an emphasis on assay mechanism and performance with some discussion on challenges and perspectives. It is hoped that this article will provide a broad coverage of DNA MTase activity assays and their latest developments and open new perspectives toward the development of DNA MTase activity assays with much improved performance for uses in molecular biology and clinical practice.

DNA Methyltransferase Activity Assays: Advances and Challenges.

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DNA Methyltransferase Activity Assays: Advances and Challenges.