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The placental gateway of maternal transgenerational epigenetic inheritance

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Abstract

While much of our understanding of genetic inheritance is based on the genome of the organism, it is becoming clear that there is an ample amount of epigenetic inheritance, which though reversible, escapes erasing process during gametogenesis and goes on to the next generation. Several examples of transgenerational inheritance of epigenetic features with potential impact on embryonic development and subsequent adult life have come to light. In placental mammals, the placenta is an additional route for epigenetic information flow. This information does not go through any meiotic reprogramming and is, therefore, likely to have a more profound influence on the organism. This also has the implication of providing epigenetic instructions for several months, which is clearly a maternal advantage. Although less well-known, there is also an impact of the embryo in emitting genetic information to the maternal system that remains well beyond the completion of the pregnancy. In this review, we discuss several factors in the context of the evolution of this mammal-specific phenomenon, including genomic imprinting, micromosaicism, and assisted reproduction. We also highlight how this kind of inheritance might require attention in the modern lifestyle within the larger context of the evolutionary process.

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Acknowledgements

This work was supported by funding from Council for Scientific and Industrial Research (CSIR) under project EpiHeD (BSC0118). G. Giridharan is gratefully acknowledged for help with figures.

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  1. CSIR - Centre for Cellular and Molecular Biology, Hyderabad , 500 007, India

    S. Purnima Sailasree, Surabhi Srivastava & Rakesh K. Mishra

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Appendix

Appendix

Epigenetic mechanisms govern genome regulation

Histones wrap the DNA around a core octamer to form nucleosomes that generate higher order chromatin folding and architecture to govern access to DNA for transcription machinery and other cellular processes. Chemical modifications of the N-terminals of the histone tails constitute a dynamic mechanism to fine tune gene expression in conjunction with DNA methylation. The methylation of lysine residues of histone H3 has been most extensively studied in the context of transcriptional control; trimethylation of lysine 4 (H3K4me3) and acetylation of lysine 9 (H3K9ac) at gene promoters and acetylation of lysine 27 (H3K27ac) and methylation of lysine 4 (H3K4me) at enhancers are strongly associated with gene activation. Similarly, trimethylation of lysine residues 27 and 9 (H3K27me3 and H3K9me3) promote gene repression through polycomb (PcG) and HP1-heterochromatin mediated mechanisms, respectively. Such modifications are catalyzed by histone acetyltransferases (HATs) / histone deacetylases (HDACs) and histone methyl transferases (HMTs) / histone demethylases (HDMs) that add or remove the acetyl or methyl groups, respectively. The presence of these marks causes recruitment of a diverse array of proteins that ultimately regulate genome activation. There are a large number of histone variants and their modifications associated with genome regulation, and these are now being studied in the light of their inheritance through reproduction (Bunkar et al. 2016); only a few of these have been investigated in placental tissues (Nelissen et al. 2011).

The methylation of CpG dinucleotides in the genome is crucial in the context of gene expression, especially at CpG islands located near gene promoters. These are mostly unmethylated to allow transcription and their methylation is associated with gene silencing. DNA methylation is brought about by DNA methyltransferases (DNMTs) that are essential for development and survival since DNMT mutants are not viable (Li et al. 1992). Demethylation of DNA is also critical during development and involves both ‘passive’ and ‘active’ mechanisms to reprogramme the foetal genome (Moore et al. 2013) by erasure of parental methylation marks and resetting of transcriptional profiles for differentiation. MicroRNAs (miRNAs) are short noncoding RNAs of approximately 20 nt length. Unlike mRNAs, they do not code for functional proteins but regulate expression of their target genes. Tissue specific miRNAs are increasingly being discovered to be associated with key biological processes. MiRNA expression is linked to DNA methylation levels (Han et al. 2007) and methylation mutants show miRNA dysregulation and vice versa (Han et al. 2013). MiRNAs also target chromatin remodelling complexes, thus directly and indirectly modulating the setting of histone marks and demonstrating the interconnectedness and redundant nature of epigenetic programmes.

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Sailasree, S.P., Srivastava, S. & Mishra, R.K. The placental gateway of maternal transgenerational epigenetic inheritance. J Genet 96, 465–482 (2017). https://doi.org/10.1007/s12041-017-0788-5

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