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Bridging the Transgenerational Gap with Epigenetic Memory

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Bridging the Transgenerational Gap with Epigenetic Memory TIGS-1027; No. of Pages 11 Review Featured Review Bridging the transgenerational gap with epigenetic memory 1,2 1,2,3 Jana P. Lim and Anne Brunet 1 Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA 2 Neurosciences Program, Stanford University School of Medicine, Stanford, CA 94305, USA 3 Glenn Laboratories for the Biology of Aging, Stanford, CA 94305, USA It is textbook knowledge that inheritance of traits is suggesting that this phenomenon is more widespread than governed by genetics, and that the epigenetic modifica- originally thought. In parallel, a growing body of work has tions an organism acquires are largely reset between revealed that exposure of parents to environmental stimuli generations. Recently, however, transgenerational epi- could affect the phenotype of several generations of des- genetic inheritance has emerged as a rapidly growing cendants, suggesting that changes in epigenetic modifica- field, providing evidence suggesting that some epige- tions induced by environmental stimuli might be passed on netic changes result in persistent phenotypes across to descendants via the gametes. Importantly, the field has generations. Here, we survey some of the most recent recently made significant progress in garnering mechanis- examples of transgenerational epigenetic inheritance tic insight into the processes underlying transgenerational in animals, ranging from Caenorhabditis elegans to epigenetic inheritance, by implicating specific chromatin humans, and describe approaches and limitations to modifications and noncoding RNA molecules. studying this phenomenon. We also review the current In this review, we survey the most recent examples of body of evidence implicating chromatin modifications epigenetic inheritance induced by genetic and environmen- and RNA molecules in mechanisms underlying this un- tal perturbations in animals (epigenetic inheritance in conventional mode of inheritance and discuss its evolu- plants has been reviewed elsewhere [14,15]). We also tionary implications. discuss the current state of progress in elucidating molec- ular mechanisms of this unconventional mode of inheri- Unconventional mode of inheritance tance, primarily focusing on chromatin and noncoding Heredity is overwhelmingly acknowledged to be governed RNAs, since the role of DNA methylation has been exten- by the laws of Gregor Mendel, with genes as the primary sively reviewed elsewhere [16–21]. We mostly focus on templates of inherited information. However, an increas- instances of nongenetic inheritance that persist for several ing number of exceptions to the rules of genetic inheritance generations (but that are not permanent), because persis- have been reported, suggesting that additional layers of tence over multiple generations reduces likelihood of information are also transmitted. During the 1920s, inher- confounding factors, such as maternal effects or direct itance of mating behavior in toads was reported by Paul exposure of the gametes to toxins. We also discuss these Kammerer [1], although this study remains controversial important limitations to our understanding of the mecha- [2]. During the 1940s, Conrad Waddington coined the term nisms underlying transgenerational epigenetic inheri- ‘epigenetic’ [3] and described inheritance of wing patterns tance. Finally, we reflect on the potential evolutionary in response to heat shock in Drosophila [4]. Shortly after, implications of this previously underappreciated mode of Alexander Brink discovered an unconventional mode of inheritance. inheritance for pigment biosynthesis in plants and termed it ‘paramutation’ [5]. The discovery of parental imprinting Epigenetic inheritance induced by alterations of the in mammals during the 1980s provided the first indication parental genome that epigenetic modifications, such as DNA methylation, Studying wild type descendants of ancestors with muta- were not entirely erased between generations and could tions in specific genomic loci has revealed that, in some underlie transgenerational epigenetic inheritance [6–11]. cases, phenotypes characteristic of the mutant ancestors It was also around this time that several cases of transge- are still present in wild type descendants (Figure 1). nerational epigenetic inheritance were reported in mice, for both exogenous transgenes and endogenous alleles Transgenerational epigenetic inheritance of color and affecting coat color [12,13]. Since these breakthrough size in mice reports, additional cases of nongenetic inheritance have Alterations in the genome, for example transcriptional been reported in species ranging from worms to mammals, activation of a chromosomal element and retrotransposon insertion, were shown to lead to transgenerational epige- Corresponding author: Brunet, A. ([email protected]). netic inheritance of Drosophila eye color [22] and mouse Keywords: transgenerational; epigenetic inheritance; chromatin; noncoding RNA; coat color [12], respectively. More recently, additional aging; fertility; metabolism; stress stimuli. 0168-9525/$ – see front matter ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tig.2012.12.008 Trends in Genetics xx (2013) 1–11 1 TIGS-1027; No. of Pages 11 Review Trends in Genetics xxx xxxx, Vol. xxx, No. x (a) which may be transmitted in a transgenerational manner for at least two generations. However, the exact mecha- × P0 nisms underlying this epigenetic memory are still unclear. +/+ –/– The importance of RNA in epigenetic inheritance in mice was bolstered by two examples of transgenerational inheri- tance of cardiac hypertrophy and organismal growth [24,25]. × F1 Injection of fertilized eggs with RNAs and miRNAs target- ing cyclin-dependent kinase 9 (Cdk9), a regulator of cardiac +/– +/+ growth, resulted in cardiac hypertrophy in the next genera- tions [24]. Furthermore, injection of miR-124, a miRNA normally expressed in the brain and involved in central Genecally nervous system development, into fertilized eggs resulted in wild type, F2 progeny that exhibited a 30% larger than normal body size phenotypically mutant [25]. This ‘giant’ phenotype persisted until the F2 genera- +/+ +/+ +/– +/– tion, after which the body size of the descendants reverted back to normal. These studies suggest that RNA-mediated epigenetic phenomena underlie the inheritance of select F3, F4, F5… phenotypes. Why some RNAs have a potential for transge- nerational effects whereas others do not is still unclear. Nongenetic inheritance of traits such as organ and animal (b) × P0 size may have crucial implications for the etiology of human hypertrophic cardiac myopathy and obesity. +/+ –/– Transgenerational epigenetic inheritance of fertility and longevity in C. elegans F1 Examples of transgenerational epigenetic inheritance in- +/– duced by alterations of the parental genome were also recently described in the nematode Caenorhabditis Self ferlizaon elegans. C. elegans is a powerful model system for the Genecally study of epigenetic memory given its rapid generation time wild type, F2 and amenability for controlling many environmental and phenotypically genetic variables. Transgenerational epigenetic inheri- mutant +/+ +/– +/– –/– tance of sterility and longevity have both been reported, and involve similar histone modifications [26,27]. First, mutants of spr-5, one of the worm orthologs of the lysine- F3, F4, F5… specific histone demethylase 1A (LSD1/KDM1), which demethylates the histone 3 lysine 4 dimethyl mark TRENDS in Genetics (H3K4me2) [28], exhibit progressive decreased brood size Figure 1. Transgenerational epigenetic inheritance induced by genetic beginning in the first generation and progressive progeny modification in ancestors. (a) Crossing scheme used in rodent studies to sterility starting around generation 20 [26]. The fertility of generate genetically wild type progeny from a mutant ancestor. (b) Crossing scheme used in worm studies to generate genetically wild type progeny from a severely sterile generations was rescued by introducing mutant ancestor. The F1 generation arises from mating between a hermaphrodite one wild type copy of spr-5 for one generation [26], indicat- and male. The F2 generation arises from the self fertilization of F1 hermaphrodites. ing that this is sufficient to induce epigenetic resetting. Key: red, wild type; blue, mutant; gray, unknown phenotype. Interestingly, accumulation of H3K4me2 and misregula- tion of spermatogenesis genes is observed in the primordial examples of transgenerational epigenetic inheritance in- germ cells (PGC) of spr-5 mutants [26]. Indeed, it has been duced by alterations of the parental genome were de- recently shown that H3K4me2 increases throughout the scribed in mice, implicating RNA in this phenomenon entire germline of spr-5 mutants [28]. Together, these [23–25]. In the first study, mice with an insertion of LacZ results suggest that failure to reset H3K4me2 marks at into the Kit gene gave rise to genetically wild type offspring select germline genes in the PGCs results in progressive that still exhibited the tail and paw color phenotype char- transgenerational sterility. acteristic of Kit mutants for at least two generations [23]. More recently, the first example of transgenerational Genetically wild type descendants of ancestors that had epigenetic inheritance of longevity was described [27]. the Kit mutant phenotype showed an altered pattern of Kit Genetically wild type descendants from ancestors that RNA expression, with RNA molecules of shorter size in are
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