Abstract
SummaryTransition 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.
Highlights
Most studies on the mechanisms that regulate human pluripotency have focused on protein-coding genes, which constitute less than 5% of the human genome
We demonstrate that a null mutation in TRIM28 leads to loss of human germline competency from primed human embryonic stem cells (hESCs), indicating that it is the ability to differentiate into the germline, not pluripotent self-renewal per se, that is sensitive to loss of TRIM28 in humans
A total of 112 UCLA1 and 48 UCLA6 clones were screened, and we identified two potential homozygous mutant hESC clones in UCLA1 that we called TRIM28 knockout (T28KO) UCLA1-9 (U1-9) and UCLA1-11 (U1-11) and one homozygous mutant in UCLA6 called T28KO U6
Summary
Most studies on the mechanisms that regulate human pluripotency have focused on protein-coding genes, which constitute less than 5% of the human genome. Recent reports have shown that TEs are dynamically expressed in human germline cells, the naive and primed states of human pluripotency, human pre-implantation embryos, and human germ cell tumors (Goke et al, 2015; Grow et al, 2015; Herbst et al, 1996; Lu et al, 2014; Theunissen et al, 2016; Wang et al, 2014). The mechanisms that regulate the dynamic expression of TEs in human pluripotency and human germline development are not well understood. LTR5_HS TEs regulate viral infection in human pluripotent stem cells, whereas LTR7-HERVHs regulate primed pluripotent stem cell self-renewal (Goke et al, 2015; Grow et al, 2015; Lu et al, 2014; Wang et al, 2014)
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