Mouse Models of Epigenetic Inheritance: Classification, Mechanisms, and Experimental Strategies

Since Weismann’s famous mouse tail-cutting experiment refuting the Lamarckian claim that acquired traits are heritable, an increasing number of mouse models have been established that have collectively provided compelling evidence that environmental factors can not only affect the mice directly exposed, but indeed also their offspring via epigenetic mechanisms. Here we outline these models together with other types of mouse epigenetic inheritance models. Our focus is on the molecular basis of epigenetic inheritance and the experimental strategies to attack mechanistic problems. In particular, we point out the hurdles hampering mechanistic studies inherent in the conventional models of epigenetic inheritance, and describe our alternative models free of such hurdles. In our models, chromatin modifications are pharmacologically inducible at simple reporter genes, which facilitates the dissection of various potential determinants of epigenetic inheritance. Our results reveal that mitotically heritable chromatin modifications can be readily established as long as the inducers act at the critical times during embryogenesis, whereas the inheritance of chromatin modifications across generations additionally requires special locus environment. Understanding the mechanisms whereby heritable epigenetic states are established and perpetuated are of tremendous biological, evolutionary, and clinical importance. Mouse models have made and will continue to make extensive contributions to the field.