Epigenetic Inheritance is Gated by Naive Pluripotency and Dppa2

Abstract

Environmental factors can trigger cellular responses that propagate across mitosis or even generations. Perturbations to the epigenome could underpin such acquired changes, however, the extent and contexts in which modified chromatin states confer heritable memory in mammals is unclear. Here we exploit a modular epigenetic editing strategy to establish de novo heterochromatin domains (epialleles) at endogenous loci and track their inheritance in a developmental model. We find that naive pluripotent phases systematically erase ectopic domains of heterochromatin via active mechanisms, which acts as an intergenerational safeguard against transmission of epialleles. Upon lineage specification however, acquired chromatin states can be probabilistically inherited under selectively favourable conditions, including propagation of p53 silencing through in vivo development. Using genome-wide CRISPR screening, we identify the mechanisms that block heritable silencing memory in pluripotent cells, and demonstrate removal of Dppa2 unlocks the potential for epigenetic inheritance uncoupled from DNA sequence. Our study outlines a mechanistic basis for how epigenetic inheritance is restricted in mammals, and reveals genomic- and developmental-contexts in which heritable memory is feasible.