Potential roles of noncoding RNAs in environmental epigenetic transgenerational inheritance

Abstract

"Epigenetic transgenerational inheritance" (ETI) has been defined as germline (sperm or egg) transmission of epigenetic information between generations in the absence of direct exposures or genetic manipulations. Among reported cases of ETI in mammals, the majority are induced by environmental factors, including environmental toxicants [e.g. agricultural fungicide vinclozolin, plastic additive bisphenol A, pesticide methoxychlor, dioxin, di-(2-ethylhexyl) phthalate, dichlorodiphenyltrichloroethane, and hydrocarbons] and poor nutritional conditions. Although the ETI phenomenon is well established, the underlying mechanism remains elusive. Putative epimutations, including changes in DNA methylation and histone modification patterns, have been reported, but it remains unclear how these epimutations are formed in the first place, and how they are memorized in the germline and then get transmitted to subsequent generations. Based on recent advances in our understanding of regulatory noncoding RNAs (ncRNAs), I propose that ncRNAs are involved in ETI, during both the initial epimutation formation and the subsequent germline transmission of epimutations. ncRNAs can function at epigenetic levels by affecting DNA methylation and histone modifications, thereby changing gene transcriptional activities, which can lead to an altered mRNA transcriptome associated with a disease phenotype. Alternatively, novel or altered ncRNA expression can cause dysregulated post-transcriptional regulation, thus directly affecting the mRNA transcriptome and inducing a disease phenotype. Sperm-borne ncRNAs are potential mediators for epigenetic memory across generations, but they alone may not be sufficient for stable transmission of epimutations across generations. Overall, research on ncRNAs in the context of ETI is urgently needed to shed light on the underlying mechanism of ETI.

Keywords: Disease etiology; Environment; Epigenetics; Gamete; Genetics; Inheritance.

Fig. 1

Schematic illustration showing the two global reprogramming events during murine development. Relative genomic methylation levels are represented on the vertical axis, whereas key stages of preimplantation and fetal germ cell development are shown on the horizontal axis. Blue and red lines denote the paternal and the maternal genomes, respectively. Dash lines represent the progression of demethylation. “dpc” stands for “days post-cotium”. This figure is adapted from (Bao and Yan, 2012).

Fig. 2

Schematic presentation of vinclozolin-induced transgenerational epigenetic inheritance of the adult onset disease phenotype. When a gestating rat (F0) is exposed to vinclozolin in the time window of primordial germ cell (PGC) reprogramming (E10.5–E13.5), epimutations [e.g. altered DNA methylation leading to the formation of differential methylation regions (DMRs)] arise and persist throughout spermatogenesis in F1 and also the post-fertilization global reprogramming in F2 embryos. These epimutations can directly cause aberrant expression of many mRNA genes, or indirectly affect mRNA expression by altering ncRNA expression. Dysregulated mRNA transcriptome results in different adult onset diseases in various organs. Epimutations and the disease phenotype can then be stably transmitted through the male germline, to not only the exposed generations (F1 and F2), but also subsequent generations that have never been exposed to vinclozolin (F3, F4, and beyond).

Fig. 3

Two potential mechanisms by which ncRNAs are involved in distal effects of differential DNA methylation regions (DMRs) on expression of multiple genes constituting an epigenetic control region (ECR). Upper panel: Environmental factors (e.g. vinclozolin) cause primary DNA methylation changes (DMRs), which, in turn, affect the expression of ncRNAs that are adjacent to the DMRs. Altered ncRNA expression then affects the expression of their target genes located distally. Lower panel: Alternatively, environmental factors (e.g. vinclozolin) can directly affect the production of ncRNAs, especially those large intergenic noncoding RNAs (lincRNAs), which are essential for sequence-specific DNA methylation (e.g. H19 lincRNA for the imprinting of H19 locus) and chromatin remodeling (e.g. HOTAIR for the epigenetic control of the Hox gene cluster). Aberrant ncRNA production leads to altered DNA methylation patterns manifested as DMRs which, in turn, affect expression of multiple mRNA genes located throughout the genome.

Fig. 4

Schematic illustration of a potential mechanism by which sperm-borne ncRNAs mediate transgenerational epigenetic inheritance. In this model, sperm-borne ncRNAs are released during paternal chromatin decondensation. In the subsequent reprogramming of the preimplantation embryos, these paternal ncRNAs may function as the “sequence guide” to direct epigenetic machineries for DNA methylation, histone modification and chromatin remodeling to set up the epigenome of the early embryo. Some, if not all, of these ncRNA-mediated epigenetic marks may possess features of those imprinted loci, and thus, can avoid erasure during the 2nd round of reprogramming in the male germline, leading to transgenerational inheritance. The key in this model is that the ncRNAs are required for reprogramming.