TRIM28-Regulated Transposon Repression Is Required for Human Germline Competency and Not Primed or Naive Human Pluripotency

Transition from primed to naive pluripotency is associated with dynamic changes in transposable element (TE) expression and demethylation of imprinting control regions (ICRs). In mouse, ICR methylation and TE expression are each regulated by TRIM28; however, the role of TRIM28 in humans is less clear. Here, we show that a null mutation in TRIM28 causes significant alterations in TE expression in both the naive and primed states of human pluripotency, and phenotypically this has limited effects on self-renewal, instead causing a loss of germline competency. Furthermore, we discovered that TRIM28 regulates paternal ICR methylation and chromatin accessibility in the primed state, with no effects on maternal ICRs. Taken together, our study shows that abnormal TE expression is tolerated by self-renewing human pluripotent cells, whereas germline competency is not. [Display omitted] •Primed and naive hESC self-renewal does not depend on TRIM28•Human germ cell formation in vitro requires TRIM28•TRIM28 differentially regulates transposons in primed and naive hESCs•DNA methylation of H19 and MEG3 requires TRIM28 In this article, Clark and colleagues show that both primed and naive hESCs are compatible with a TRIM28 deletion, despite massive deregulation of transposable elements. However, human germline competency and paternal imprint methylation are compromised upon loss of TRIM28.