epigenetic inheritance mechanisms

Med. (2016), a lack of protein, iron, choline, or zinc can precipitate several cognitive deficits and even intellectual disabilities and autistic symptoms in the offspring. 24, 1055–1064. 2019 Sep 11;25(5):518-540. doi: 10.1093/humupd/dmz017. Sex-specificity in transgenerational epigenetic programming. Collectively, epigenetic mechanisms determine chromatin architecture, accessibility of genetic loci to transcriptional machinery, and gene expression levels. Of the molecular processes that are implicated in this phenomenon, well-known (methylation) and novel (non-coding RNA, ncRNA) regulatory mechanisms are converging. Moreover, certain miRNAs (primarily Let-7, miR-30 and miR-16 but also miR-34a) are maternally inherited and depend on maternal miRNA-processing machinery (Tang et al., 2007; Soni et al., 2013). Epigenetic mechanisms can enable heritable changes in gene expression that can increase both phenotypic and genetic variance. Health 5:2. doi: 10.1186/1753-2000-5-2, van Otterdijk, S. D., Mathers, J. C., and Strathdee, G. (2013). Maintenance and de novo methylation and active and passive demethylation are crucial for embryonic development and epigenetic inheritance. Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation. Notably, this phenomenon implies even dynamic and short-term regulation of gene expression, mediated by the action—almost in real time—of regulatory proteins, called transcription factors, such as c-fos, c-jun, ZENK and CREB. 33, 46–57. Abstract. Such paradigms are essential in order to begin to use genetics to unpick the mechanistic bases of how epigenetic information may be transmitted between generations; indeed great strides have been made … Bethesda, MD 20894, Copyright Female exposure to a certain environmental factor during pregnancy might even affect the offspring’s germ cells directly, for which reason only the fourth generation can be considered “event-free” and unsullied. (2012). Consequently, the totipotency of the zygote is established and maintained across the first several cell divisions. Epigenetics • Genetics (nature)-inheritance of genes • Epigenetics (nurture)-inheritance of changes in gene expression Transgenerational epigenetic influences of paternal environmental exposures on brain function and predisposition to psychiatric disorders. Note that this epigenetic inheritance mechanism differs from better known epigenetic mechanisms such as DNA methylation in that it does not affect the phenotype (TL) by modulating gene expression, but instead through direct inheritance of the phenotype itself and therefore has also been referred to as “epigenetic-like” . Print 2021 Feb. Wan QL, Meng X, Dai W, Luo Z, Wang C, Fu X, Yang J, Ye Q, Zhou Q. Sci Adv. Paternal environmental enrichment transgenerationally alters affective behavioral and neuroendocrine phenotypes. doi: 10.1016/j.tig.2016.11.001, Hu, M., Richard, J. E., Maliqueo, M., Kokosar, M., Fornes, R., Benrick, A., et al. Although the epigenetic mechanisms underlying parental environment‐induced transgenerational effects have been better illuminated in invertebrates, differences arising from paternal and maternal germline transmission and differences in the epigenetic inheritance outcomes between genders have been most frequently reported in mammals. Paralleling Crews (2008) and van Otterdijk and Michels (2016), the second form of environmental action (i.e., phylogenetic adaptation) can be divided into two categories of “indirect epigenetics (IE):” within and across. In higher eukaryotes, DNA methylation usually points to methylation of cytosines, which is catalysed by cytosine methyltransferases yielding 5-methylcytosine (m 5 C) after DNA replication. Similarly, by microarray, the expression of several miRNAs in the blood of bipolar and depressed patients has been measured, wherein disorder-specific and commonly altered miRNAs have been identified (Maffioletti et al., 2016). doi: 10.1038/nrn3879, Issler, O., Haramati, S., Paul, E. D., Maeno, H., Navon, I., Zwang, R., et al. (2014). doi: 10.1016/j.rbmo.2014.03.002, PubMed Abstract | CrossRef Full Text | Google Scholar, Amaral, P. P., Dinger, M. E., and Mattick, J. S. (2013). There are different mechanisms through which the process occur and are used as research tools. How does epigenetic inheritance occur concretely? Because they can be modified by the environment and may be inherited from parent to offspring, epigenetic mechanisms are a prime candidate for mediating transgenerational inheritance. (2013); miR-193–5p, miR-204, miR-29c, miR-30a, miR-30c, miR-32, miR-375, miR-532–3p and miR-698) were injected into a zygote, and similar glucocorticoid levels and behavioral responses as in the offspring of stressed male mice were observed in the offspring (Rodgers et al., 2015). 2, 455–467. Functions of DNA methylation: islands, starts sites, gene bodies and beyond. Moreover, miR-16 is downregulated in the locus coeruleus and the hippocampus (Launay et al., 2011). Nongenetic inheritance and transgenerational epigenetics. Brain Res. (2016). (2014), there is much evidence of altered miRNA expression in depression and greater expression after antidepressant treatment (e.g., miR-16, miR-30, miR-128, miR-132, miR335, miR-494, miR182). We focus on the transmission of psychopathologies—especially in relation to disruptions in the stress response—because they have long been the center of the historical debate over the weights of genes and the environment in such processes as individual development and inheritance, given their complex nature and clear experience sensitivity. 49, 53–59. doi: 10.1038/nsmb.1391, Skinner, M. K. (2008). Epigenetic phenomena, and in particular heritable epigenetic changes, or transgenerational effects, are the subject of much discussion in the current literature. Mol. Elevated paternal glucocorticoid exposure alters the small non-coding RNA profile in sperm and modifies anxiety and depressive phenotypes in the offspring. Mechanisms, timescales and principles of trans-generational epigenetic inheritance in animals Animal development does not start with a blank slate. Dev. (2016). This appears to be particularly true for the first several months of life, and as we discuss, many epigenetic studies have focused on sensitive periods (Jawahar et al., 2015; Maccari et al., 2017). First, we will describe the evidence for the phenomenon of epigenetics, then define it, and briefly summarize epigenetic mechanisms. Epigenomics 8, 1389–1398. Parental life events cause behavioral difference among offspring: adult pre-gestational restraint stress reduces anxiety across generations. This catalytic event produces a stem-loop structure, the precursor miRNA (pre-miRNA). eCollection 2021 Feb 11. doi: 10.1016/j.neubiorev.2011.04.012, Cardoso, M. C., and Leonhardt, H. (1999). MicroRNA-34 contributes to the stress related behavior and 5-HT Prefrontal/GABA amygdalar system through regulation of Corticotropin-Releasing Factor Receptor 1. doi: 10.1016/j.tips.2016.10.004, Okamura, K., Chung, W. J., Ruby, J. G., Guo, H., Bartel, D. P., and Lai, E. C. (2008). Second, we explain the major epigenetic mechanisms implicated in transgenerational inheritance. Epigenetic information refers to heritable changes in gene expression that occur without modifications at the DNA sequence level. In these cases, such alterations in epigenetic markers could be caused by genetic polymorphisms, epigenetic adaptation to certain environmental conditions, or both. Sci. doi: 10.1016/j.neuroscience.2016.05.042, Maffioletti, E., Cattaneo, A., Rosso, G., Maina, G., Maj, C., Gennarelli, M., et al. DE refers to changes that occur in the lifespan of an individual, due to direct experiences with his environment. Genet. Notably, miRNAs control de novo DNA methylation by regulating transcriptional repressors (Sinkkonen et al., 2008). Conradt et al. Neurosci. The peculiar nature of epigenetics could allow us to intervene at various levels synchronously, thus applying more effective synergistic activity against complex diseases, which have not been able to be properly understood or approached until now—particularly on the molecular level. Genet. (2016). doi: 10.1038/nrg3354, Soni, K., Choudhary, A., Patowary, A., Singh, A. R., Bhatia, S., Sivasubbu, S., et al. Epigenetics 11, 150–162. 53, 711–723. Similarly, oocytes could transmit epigenetic marks of maternal experiences that occur before pregnancy. PLoS One 8:e66318. Peripheral whole blood microRNA alterations in major depression and bipolar disorder. The levels of certain stress-related proteins have been analyzed. These effects may even endure for several generations. DNA methyltransferase is actively retained in the cytoplasm during early development. Maternal cigarette smoking during pregnancy is associated with downregulation of miR-16, miR-21 and miR-146a in the placenta. There is extensive literature on epigenetics, but no consensus exists with regard to how and what can (and must) be considered to study and define epigenetics processes and their inheritance. 368:20110330. doi: 10.1098/rstb.2011.0330, Seitz, H., Royo, H., Bortolin, M. L., Lin, S. P., Ferguson-Smith, A. C., and Cavaillé, J. Inverse correlation of brain and blood BDNF levels in a genetic rat model of depression. Dosage Compensation. Epigenetics generally refers to four mechanisms. Recently, the miRNA expression patterns in placental (Gu et al., 2013; Maccani et al., 2013) and germ cells (Soni et al., 2013; Rodgers et al., 2015) have been implicated in fetal programming, and increasing evidence is considering the function of miRNAs in mediating transgenerational epigenetic inheritance of stress responsivity (Babenko et al., 2015; Fraser and Lin, 2016; Pang et al., 2017; Yeshurun and Hannan, 2018). Thus, there is no reason why a similar therapeutic approach should be overlooked for epigenetic abnormalities that affect an individual at early age and even during fetal development. Neurosci. (2017). doi: 10.1038/nature07015, Painter, R. C., Osmond, C., Gluckman, P., Hanson, M., Phillips, D. I., and Roseboom, T. J. DNA methylation is involved in many processes, particularly those that are important for early development, such as genomic imprinting, X-chromosome inactivation, and transposon silencing (Smith and Meissner, 2013). doi: 10.1371/journal.pone.0031901, Masri, S., and Sassone-Corsi, P. (2013). This dual nature of ncRNAs implicates them as “change amplifiers.” In this sense, ncRNAs are similar to transcription factors. However, the debate over whether ncRNAs should be considered epigenetic factors continues (Kovalchuk, 2012). Reduced function of the serotonin transporter is associated with decreased expression of BDNF in rodents as well as in humans. Curr. This should be considered the most intuitive means of transgenerational transmission of information—the most naïve but still undeniable Lamarckian addition to Darwinian evolution. Embryonic stem cell miRNAs and their roles in development and disease. R. Soc. (2007). Effects of Environment and Lifestyle Factors on Anovulatory Disorder. doi: 10.1016/j.pnpbp.2013.07.014, Dorrington, S., Zammit, S., Asher, L., Evans, J., Heron, J., and Lewis, G. (2014). Wider environmental effectors, such as parental style and cultural aspects, must be considered with caution. 14, 523–534. Maternal separation, considered the archetype of early life stress, is associated with alterations in methylation patterns in several genes that are implicated in anxiety (Murgatroyd et al., 2009; Kember et al., 2012; Wu et al., 2014)—notably corticotropin-releasing factor (CRF) and its receptor (Chen et al., 2012; Sotnikov et al., 2014). Adv. 10, 682–688. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. doi: 10.1002/dev.420140607, Gapp, K., von Ziegler, L., Tweedie-Cullen, R. Y., and Mansuy, I. M. (2014). This site needs JavaScript to work properly. (2010). Paternal experiences can induce changes in the sperm that impact, for example, the HPA axis in progeny, their cognitive abilities, and their cellular and molecular processes (Yeshurun and Hannan, 2018). J. Med. This subfamily of dioxygenases catalyzes the oxidation of 5mC to hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and finally 5-carboxylcytosine (5caC). Biomed. Epigenetic changes that can be transmitted can belong to any of the previous categories (DE and IE). Genet. This possibility implies that it would be better to apply several types of environmental conditions on all possible levels. Stress 14, 590–603. Environmental exposure to vinclozolin, an endocrine disruptor that is commonly used as an agricultural fungicide, increases sensitivity to stress—namely, anxious behavior—in the F3 generation (Crews et al., 2012). Brain Behav. What is an epigenetic transgenerational phenotype? As reviewed by Faa et al. Sci. Pri-miRNAs are attacked by the microprocessor complex, composed of RNase III (Drosha) and DGCR8 (Pasha). In this Review, we discuss the examples of MEI in mammals, including mammalian epigenome reprogramming, and the molecular mechanisms of MEI in vertebrates in general. Psychiatry 73, 44–53. IVF requires superovulation and the use of an artificial culture, which could alter the programing of gametes (Bohacek and Mansuy, 2015). Psychol. Induction of epigenetic alterations by dietary and other environmental factors. 28, 1057–1068. Short et al. Natl. Strain-dependent variations in stress coping behavior are mediated by a 5-HT/GABA interaction within the prefrontal corticolimbic system. Similarly, Andolina et al. 42, 877–889. 27, 391–402. (2013). Biol. Oxytocin receptor gene methylation: converging multilevel evidence for a role in social anxiety. 41, 803–807. Transl. Drosha cleaves pri-miRNA into a shorter transcript, whereas Pasha stabilizes the interaction between Drosha and pri-mRNA. Early-life experiences and the development of adult diseases with a focus on mental illness: the human Birth theory. Our discussion of the chief methods that are used to study epigenetic inheritance highlights the most compelling technical and theoretical problems of this discipline. After sex determination, gametogonia DNA is remethylated through a second de novo methylation step. (2010). Endocrinology 155, 1751–1762. Although these processes are strongly interconnected and can overlap on multiple levels in a complex real system, here they are treated as discrete and sequential, for the sake of clarity. Z., Ning, S. F., Miao, Y. L., Yuan, H. J., et al. doi: 10.1016/j.cobeha.2017.02.007, Peng, H., Shi, J., Zhang, Y., Zhang, H., Liao, S., Li, W., et al. Genome Biol. 304, E836–E843. The elimination and restoration of methylation markers happen in two steps. doi: 10.3109/10408444.2012.725244, Tang, F., Kaneda, M., O’Carroll, D., Hajkova, P., Barton, S. C., Sun, Y. (2013). (2010). A., Li, S., Hartley, D. M., and Feig, L. A. Next, we will cover the epigenetic phenomenon of genomic imprinting, and finally, we will discuss how environmental perturbations in early life can result in disease later in life. Parents’ stressful experiences can influence an offspring’s vulnerability to many pathological conditions, including psychopathologies, and their effects may even endure for several generations. doi: 10.1002/dev.20592, Liu, G., Mattick, J. S., and Taft, R. J. It has recently been established that epigenetic effects can be inherited from one generation to the next. Epigenetics is the occurrence of changes in gene expression independent of the DNA sequence. A., and Ventura, A. Recent results (Andolina et al., 2018) highlight the molecular mechanisms of this phenomenon, completing this model: when a stressor is encountered, miR-34 levels influence which coping strategy will be implemented through its inhibition of CRFR1 expression in DRN, which in turn regulates the balance in cortico-subcortical 5-HT/GABA activity that ultimately governs motivation and its behavioral output (Puglisi-Allegra and Andolina, 2015). The discussed techniques are summarized in Table 2. Only when it was demonstrated that epigenetic modifications could be inherited did the ontogenetic (i.e., environmental influences) and phylogenetic (i.e., genetic determinants) worlds—which for years had approached each other in an asymptotic, exhaustive manner—finally merge at a new, theoretical intersection: epigenetic inheritance.

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