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      Epigenetics: A key paradigm in reproductive health

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          Abstract

          It is well established that there is a heritable element of susceptibility to chronic human ailments, yet there is compelling evidence that some components of such heritability are transmitted through non-genetic factors. Due to the complexity of reproductive processes, identifying the inheritance patterns of these factors is not easy. But little doubt exists that besides the genomic backbone, a range of epigenetic cues affect our genetic programme. The inter-generational transmission of epigenetic marks is believed to operate via four principal means that dramatically differ in their information content: DNA methylation, histone modifications, microRNAs and nucleosome positioning. These epigenetic signatures influence the cellular machinery through positive and negative feedback mechanisms either alone or interactively. Understanding how these mechanisms work to activate or deactivate parts of our genetic programme not only on a day-to-day basis but also over generations is an important area of reproductive health research.

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          Most cited references226

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          Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting.

          Imprinted genes are epigenetically marked during gametogenesis so that they are exclusively expressed from either the paternal or the maternal allele in offspring. Imprinting prevents parthenogenesis in mammals and is often disrupted in congenital malformation syndromes, tumours and cloned animals. Although de novo DNA methyltransferases of the Dnmt3 family are implicated in maternal imprinting, the lethality of Dnmt3a and Dnmt3b knockout mice has precluded further studies. We here report the disruption of Dnmt3a and Dnmt3b in germ cells, with their preservation in somatic cells, by conditional knockout technology. Offspring from Dnmt3a conditional mutant females die in utero and lack methylation and allele-specific expression at all maternally imprinted loci examined. Dnmt3a conditional mutant males show impaired spermatogenesis and lack methylation at two of three paternally imprinted loci examined in spermatogonia. By contrast, Dnmt3b conditional mutants and their offspring show no apparent phenotype. The phenotype of Dnmt3a conditional mutants is indistinguishable from that of Dnmt3L knockout mice, except for the discrepancy in methylation at one locus. These results indicate that both Dnmt3a and Dnmt3L are required for methylation of most imprinted loci in germ cells, but also suggest the involvement of other factors.
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            Active DNA demethylation: many roads lead to Rome.

            DNA methylation is one of the best-characterized epigenetic modifications and has been implicated in numerous biological processes, including transposable element silencing, genomic imprinting and X chromosome inactivation. Compared with other epigenetic modifications, DNA methylation is thought to be relatively stable. Despite its role in long-term silencing, DNA methylation is more dynamic than originally thought as active DNA demethylation has been observed during specific stages of development. In the past decade, many enzymes have been proposed to carry out active DNA demethylation and growing evidence suggests that, depending on the context, this process may be achieved by multiple mechanisms. Insight into how DNA methylation is dynamically regulated will broaden our understanding of epigenetic regulation and have great implications in somatic cell reprogramming and regenerative medicine.
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              DNA methylation of retrotransposon genes is regulated by Piwi family members MILI and MIWI2 in murine fetal testes.

              Silencing of transposable elements occurs during fetal gametogenesis in males via de novo DNA methylation of their regulatory regions. The loss of MILI (miwi-like) and MIWI2 (mouse piwi 2), two mouse homologs of Drosophila Piwi, activates retrotransposon gene expression by impairing DNA methylation in the regulatory regions of the retrotransposons. However, as it is unclear whether the defective DNA methylation in the mutants is due to the impairment of de novo DNA methylation, we analyze DNA methylation and Piwi-interacting small RNA (piRNA) expression in wild-type, MILI-null, and MIWI2-null male fetal germ cells. We reveal that defective DNA methylation of the regulatory regions of the Line-1 (long interspersed nuclear elements) and IAP (intracisternal A particle) retrotransposons in the MILI-null and MIWI2-null male germ cells takes place at the level of de novo methylation. Comprehensive analysis shows that the piRNAs of fetal germ cells are distinct from those previously identified in neonatal and adult germ cells. The expression of piRNAs is reduced under MILI- and MIWI2-null conditions in fetal germ cells, although the extent of the reduction differs significantly between the two mutants. Our data strongly suggest that MILI and MIWI2 play essential roles in establishing de novo DNA methylation of retrotransposons in fetal male germ cells.
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                Author and article information

                Journal
                Clin Exp Reprod Med
                Clin Exp Reprod Med
                CERM
                Clinical and Experimental Reproductive Medicine
                The Korean Society for Reproductive Medicine
                2233-8233
                2233-8241
                June 2016
                23 June 2016
                : 43
                : 2
                : 59-81
                Affiliations
                [1 ]Translational Research Laboratory, School of Biological Sciences, Dr. Hari Singh Central University, Sagar, India.
                [2 ]Reproductive Physiology Laboratory, Centre for Advanced Studies, University of Rajasthan, Jaipur, India.
                [3 ]Department of Molecular Biology, National Institute for Research in Environmental Health (ICMR), Bhopal, India.
                Author notes
                Corresponding author: Pradyumna Kumar Mishra. Department of Molecular Biology, National Institute for Research in Environmental Health (ICMR), Kamla Nehru Hospital Building (GMC Campus), Bhopal 462 001 (MP), India. Tel: +91-755-2533106, Fax: +91-755-2533976, pkm_8bh@ 123456yahoo.co.uk
                Article
                10.5653/cerm.2016.43.2.59
                4925870
                27358824
                7fccff00-1f8c-4ab3-a27b-16e5bebb730f
                Copyright © 2016. The Korean Society for Reproductive Medicine

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 03 January 2016
                : 06 February 2016
                : 16 March 2016
                Funding
                Funded by: Department of Biotechnology, Council of Scientific and Industrial Research, CrossRef http://dx.doi.org/10.13039/501100001412;
                Funded by: Department of Science & Technology, Government of India;
                Categories
                Review

                Obstetrics & Gynecology
                dna methylation,epigenomics,histone code,micrornas
                Obstetrics & Gynecology
                dna methylation, epigenomics, histone code, micrornas

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