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Epigenetics in Sperm, Epigenetic Diagnostics, and Transgenerational Inheritance
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Jennifer L. M. Thorson, Millissia Ben Maamar, Michael K. Skinner
The environment has been shown to be one of the most critical factors to impact the biology of an organism. An exposure to one or multiple environmental factors (e.g., nutrition, toxicants, stress) can trigger changes in the transcriptome and impact the development of pathologies or phenotypic variation. As described above, epigenetic factors are the molecular mechanisms an organism uses to respond to an environmental change with modifications in gene expression. Most environmental factors and toxicants do not possess the capacity to alter DNA sequence or promote genetic mutations (67). However, the environment is able to dramatically influence epigenetic processes which then affect gene expression and development. In human and animal models, several studies have demonstrated that exposure to certain environmental toxicants at a specific window of development, especially when the epigenome is reprogramming, can affect the mechanisms involved in the establishment of the sperm epigenome. Since the sperm epigenome has been shown to be crucial for the fertility of the individuals, any variations could be related to male infertility (68). Some epimutations have also been shown to be transmitted via the sperm to the offspring and subsequent generations which has been defined as the concept of epigenetic transgenerational inheritance (4,6,69). Therefore, epigenetics provides a molecular mechanism for the environment to directly alter the biology of an organism (70). The presence of an altered epigenetic factor at a specific chromosomal location in response to an environmental factor is called an “epimutation” (71).
Role of Histone Methyltransferase in Breast Cancer
Published in Meenu Gupta, Rachna Jain, Arun Solanki, Fadi Al-Turjman, Cancer Prediction for Industrial IoT 4.0: A Machine Learning Perspective, 2021
Surekha Manhas, Zaved Ahmed Khan
Characterization of genomic tumor is generally carried out through distinct changes in methylation that have also been marked as the term “epimutations”. Genomic instability is linked to hypomethylation, especially at the centromeric repeat sequences [2]. The other epimutation class is characterized explicitly by individual gene local hypermethylation, which has been related to deviant gene silencing [3]. The role of epimutations has been very well illustrated in various types of drastic cancer and tumorigenesis. For example, DNA mismatch inactivation is mainly associated with epigenetic silencing in sporadic colon cancer rather than gene mutation [4]. E-cadherin methylation has also played a central markable role in the process of metastasis as well as in invasion in case of issues associated with breast cancer [5]. These kinds of epimutation changes rarely appear in healthy tissue, which shows the high tumor specificity of epigenetic therapies.
Epigenetic and Assisted Reproduction Epidemiological Studies
Published in Cristina Camprubí, Joan Blanco, Epigenetics and Assisted Reproduction, 2018
Four different types of molecular changes associated with ImpDis are currently known (Figure 7.1). Three of them represent genomic alterations, and include large deletions or duplications (copy number variations, CNVs) affecting DMRs, point mutations in the genes themselves, or uniparental disomies (UPDs; i.e., the inheritance of the two homologues from a chromosome pair from the same parent). These alterations of the DNA itself can occur sporadically, or can be inherited, in the latter case a parent-of-origin specific manifestation of the phenotype has to be considered. In contrast, epimutations as the fourth class of molecular alterations in ImpDis are defined as changes which affect the expression of imprinted genes, but not the genomic sequence of the DMR itself. These epimutations either consist of a hypomethylation (loss of methylation, LOM) or a hypermethylation (gain of methylation, GOM), and thereby influence the expression of the imprinted genes. The transitions between point mutations/CNVs and epimutations are fluid, as meanwhile several epimutations have been reported which are the result of a genomic mutation in another chromosomal region or gene influencing the methylation pattern of a DMR. The underlying mutations of these so-called secondary epimutations can either be localized physically close to the altered DMR in cis (6), or in a region on another chromosome (e.g., mutations in ZFP57 genes (7). Molecularly, secondary epimutations cannot be discriminated from primary epimutations as the aberrantly methylated DMR does not show obvious genomic changes. Thus, the identification of an epimutation in an ImpDis patient requires a careful molecular and anamnestic follow-up (e.g., for chromosome 11p15 associated ImpDis [8]), and it becomes increasingly apparent that isolated and sporadic epimutations rather belong to the group of primary epimutations, whereas a familial accumulation and an increased number of spontaneous abortions in a family indicates a genomic cause of the epimutation.
Microsatellite Instability and Promoter Hypermethylation of DNA repair genes in Hematologic Malignancies: a forthcoming direction toward diagnostics
Published in Hematology, 2018
Priyanjali Bhattacharya, Trupti N. Patel
The major arena for methylation assay is in differential diagnosis where conventional tests turn out to be difficult to conclude [42]. Immune therapy response for DNA repair deficiency caused by mutation and methylation recently opened up a new vision in MSI-positive colorectal tumor [43–46], but whether the same is true for blood-related cancers needs to be elucidated. Diagnostically screening of biologically related family members for MSI markers and epimutation can also help us to evaluate the possible clause in hematologic malignancies.
From tangled banks to toxic bunnies; a reflection on the issues involved in developing an ecosystem approach for environmental radiation protection
Published in International Journal of Radiation Biology, 2022
Carmel E. Mothersill, Deborah H. Oughton, Paul N. Schofield, Michael Abend, Christelle Adam-Guillermin, Kentaro Ariyoshi, Nicholas A. Beresford, Andrea Bonisoli-Alquati, Jason Cohen, Yuri Dubrova, Stanislav A. Geras’kin, Tanya Helena Hevrøy, Kathryn A. Higley, Nele Horemans, Awadhesh N. Jha, Lawrence A. Kapustka, Juliann G. Kiang, Balázs G. Madas, Gibin Powathil, Elena I. Sarapultseva, Colin B. Seymour, Nguyen T. K. Vo, Michael D. Wood
DNA damage is a recognized outcome of radiation exposure, together with a variety of key processes such as epigenetic modifications, including DNA methylation and transcriptomic (mRNA) and post-transcriptomic (small RNA and long non-coding RNA) measurements (e.g. Schofield and Kondratowicz 2018). However their ecological relevance is a matter of debate. DNA damage poses a direct threat as a precursor of mutation. Mutations are typically neutral to mildly deleterious. Most of the time they will cause no effect, - due to redundancy in the genetic code and the large proportion of the genome that does not perform any known function, - or have effects that (a) are non-lethal, and (b) only reduce performance of developmental, behavioral and physiological systems, rather than total impairment of those systems. DNA damage could also affect reproduction and survival because DNA repair requires a diversion of energy from other activities (Roff 2001). Epigenetic variation may however be expected to have a potentially more significant effect as epimutation is in its nature pleiotropic and affects the expression of many genes (Schofield and Kondratowicz 2018). Epigenetic changes have the potential to mediate toxicological, and transgenerational deleterious effects of exposure to ionizing radiation when they suppress the expression of genes otherwise useful for the organism. In principle, however, epigenetic changes can also favor a plastic response to ionizing radiation that can later be accommodated into an evolutionary one (Bossdorf et al. 2008). The translation of these organism-level effects to the population level is however complex. For example, higher mortality can be compensated by immigration from outside of the contaminated areas, and countered by reduced intra-specific competition and lower predation pressure. Time is also an important factor. In a laboratory, organisms are usually measured a short time after exposure, whereas field studies are often conducted years after the contamination event.