Trends in Genetics
Volume 29, Issue 3, March 2013, Pages 176-186
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Feature Review
Bridging the transgenerational gap with epigenetic memory

https://doi.org/10.1016/j.tig.2012.12.008Get rights and content

It is textbook knowledge that inheritance of traits is governed by genetics, and that the epigenetic modifications an organism acquires are largely reset between generations. Recently, however, transgenerational epigenetic inheritance has emerged as a rapidly growing field, providing evidence suggesting that some epigenetic changes result in persistent phenotypes across generations. Here, we survey some of the most recent examples of transgenerational epigenetic inheritance in animals, ranging from Caenorhabditis elegans to humans, and describe approaches and limitations to studying this phenomenon. We also review the current body of evidence implicating chromatin modifications and RNA molecules in mechanisms underlying this unconventional mode of inheritance and discuss its evolutionary implications.

Section snippets

Unconventional mode of inheritance

Heredity is overwhelmingly acknowledged to be governed by the laws of Gregor Mendel, with genes as the primary templates of inherited information. However, an increasing number of exceptions to the rules of genetic inheritance have been reported, suggesting that additional layers of information are also transmitted. During the 1920s, inheritance of mating behavior in toads was reported by Paul Kammerer [1], although this study remains controversial [2]. During the 1940s, Conrad Waddington

Epigenetic inheritance induced by alterations of the parental genome

Studying wild type descendants of ancestors with mutations in specific genomic loci has revealed that, in some cases, phenotypes characteristic of the mutant ancestors are still present in wild type descendants (Figure 1).

Epigenetic inheritance induced by metabolic changes in parents

Interestingly, epigenetic inheritance can also be induced by environmental changes in parents. The past few years have seen a flurry of reports on the inheritance of acquired metabolic phenotypes resulting from over- or undernutrition in parents. To avoid potential confounds of in utero and altered maternal caretaking, studies have investigated transgenerational inheritance of metabolic physiology through the paternal (Figure 2a) or the maternal (Figure 2b) lineage. In such schemes, the gametes

Epigenetic inheritance of phenotypes induced by environmental stress

In Drosophila, heat shock and osmotic stress induce phenotypes, including wing changes and the disruption of heterochromatin, that are transgenerationally heritable for multiple generations 4, 40. The epigenetic inheritance of heat shock-induced chromatin disruption occurs via drosophila activation transcription factor 2 (dATF-2) [40], a transcription factor that functions in heterochromatin nucleation [41]. Cellular stress induces the phosphorylation of dATF-2 and, thus, its release from

Epigenetic inheritance of RNAs derived from a viral sequence

A recent study in C. elegans reported transgenerational inheritance of small RNAs derived from a virus [43]. The authors generated a worm transgenic line expressing the Flock House virus, which results in the production of small-interfering RNAs derived from the virus (viRNAs). These viRNAs serve to silence the viral genome. Interestingly, the silencing effect of viRNAs is transmitted in an epigenetic manner to several generations of descendants [43]. The viRNAs themselves are transmitted in a

Depressive-like behaviors

Exposure to prenatal psychological stress in mice appears to impact F2 generation offspring in an epigenetic manner [44]. F2 males from fathers that were exposed to prenatal stress exhibited a brain gene expression profile that was more similar to that of control females than of control males (termed ‘dysmasculinization’) [44]. In particular, three miRNAs targeting β-glycan, a member of the transforming growth factor (TGF) β family known to regulate release of gonadal hormones, were

DNA methylation

DNA methylation can be transmitted across generations, for example in genomic imprinting, and could thus underlie transgenerational inheritance of specific traits 16, 17, 18, 19, 21 (Figure 3, Table 1). Indeed, several studies discussed here have observed heritable changes in DNA methylation at specific loci, for example in response to a high-fat diet and maternal and postnatal stress 32, 34, 45. By contrast, other studies have found DNA methylation to be minimally affected, for example after

Concluding remarks

Transgenerational epigenetic inheritance has been observed for a series of different phenotypes and can result from a variety of genetic or environmental manipulations in either parent. Many recent studies aimed at elucidating the mechanism of this unconventional mode of inheritance have identified promising candidates for mediating these lasting epigenetic effects, including histone modifications and noncoding RNAs. It is possible that different instances of transgenerational epigenetic

Acknowledgments

We would like to thank E. Greer, S. Han, B. Benayoun, and D. Valenzano for critical reading of this manuscript, and G. Sherlock and A. Sidow for advice on potential evolutionary implications. Supported by NIH DP1-AG044848, NIH R01-AG031198, and the Glenn Laboratories for the Biology of Aging at Stanford University. J.P.L. is supported by NIH T32-MH020016 and a NSF Graduate Research Fellowship.

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