Chapter 8 - Towards the Molecular Mechanisms of Transgenerational Epigenetic Inheritance: Insights from Transgenic Mice

Abstract

In transgenerational epigenetic inheritance (TEI), epigenetic perturbations induced in gametes are transmitted not only to the ensuing organisms but also to their offspring via the germline. Such heritable perturbations, rarely arising spontaneously, seem fairly common following exposures to environmental factors, which is remarkable given the global epigenetic reprogramming during the subsequent embryogenesis intended at clearing these perturbations to restore the totipotency of the epigenome. A major mechanism of epigenetic inheritance is based on self-perpetuating chromatin marks, which is the focus of this review. A number of parameters may conspire to enable a chromatin mark to be inherited, including the timing of introduction of the chromatin modification, the chemical nature of the modification, and the sequence, copy number, and location of the underlying gene. Transgenic models provide a tractable system for dissecting these parameters. TEI in mammals was first observed in traditional transgenic mice, where, following germline transmission or genetic background switching, constitutively active, randomly integrated transgenes of various copy numbers become heritably silenced apparently via CpG methylation. Recently, inducible TEI models have been established using tetracycline-regulated reporter genes and site-specific integration, where multiple parameters affecting TEI can be precisely controlled. It has been found that mitotic inheritance of epigenetic modifications is dependent on the timing of the induction of the modifications, whereas transgenerational inheritance additionally depends on the location of the modifications. In contrast, other parameters examined appear to be irrelevant. In particular, both repressive and activating chromatin modifications can be transgenerationally inherited at the Col1a1 locus, which is unprecedented and points to a novel mechanism of TEI. The newly available Cas-9-based gene-targeting methods will make it possible to apply this basic genetic strategy on a large scale.