Role of Tet1 in erasure of genomic imprinting

Abstract

Genomic imprinting is an allele-specific gene expression system important for mammalian development and function 1. The molecular basis of genomic imprinting is allele-specific DNA methylation 1,2. While it is well known that the de novo DNA methyltransferases Dnmt3a/b are responsible for the establishment of genomic imprinting 3, how the methylation mark is erased during primordial germ cell (PGC) reprogramming remains a mystery. Tet1 is one of the ten-eleven translocation family proteins, which have the capacity to oxidize 5-methylcytosine (5mC) 4-6, specifically expressed in reprogramming PGCs 7. Here we report that Tet1 plays a critical role in the erasure of genomic imprinting. We show that despite their identical genotype, progenies derived from mating between Tet1-KO males and wild-type females exhibit a number of variable phenotypes including placental, fetal and postnatal growth defects, and early embryonic lethality. These defects are, at least in part, caused by the dysregulation of imprinted genes, such as Peg10 and Peg3, which exhibit aberrant hypermethylation in the paternal allele of differential methylated regions (DMRs). RNA-seq reveals extensive dysregulation of imprinted genes in the next generation due to paternal loss function of Tet1. Genome-wide DNA methylation analysis of E13.5 PGCs and sperms of Tet1-KO mice revealed hypermethylation of DMRs of imprinted genes in sperm, which can be traced back to PGCs. Analysis of the DNA methylation dynamics in reprogramming PGCs suggests that Tet1 functions to wipe out remaining methylation, including imprinted genes, at the late reprogramming stage. We further provide evidence supporting Tet1's role in the erasure of paternal imprints in female germline. Thus, our study establishes a critical function of Tet1 in genomic imprinting erasure.

Simultaneous deletion of the methylcytosine oxidases Tet1 and Tet3 increases transcriptome variability in early embryogenesis

“…With one exception (20), most previous work in this area has focused on loss of function of individual TET proteins (17,19,25,42). Because TET proteins clearly function redundantly (20,25,43), we preferred to examine mice with a very substantial loss of TET function during early embryonic development.…”

When is incomplete epigenetic resetting in germ cells favoured by natural selection?

“…Such effects are increasingly observed in animals and, in particular, plants (reviews in [4,5,17,19,42]), where studies of experimental lines suggest that induced patterns of DNA methylation are readily inherited [11]. Similarly, in mammals, DNA sequences can resist reprogramming [43,44], and the extent of demethylation is regulated by the methylation machinery [45,46]. Thus, although we often expect transgenerational epigenetic inheritance to be maladaptive (or fitness neutral), the extent of resetting could evolve in response to selection.…”

Modulating Epigenetic Memory through Vitamins and TET: Implications for Regenerative Medicine and Cancer Treatment

“…Given that loss of imprinting is a known driver of developmental disease and cancer [64,65], its occurrence in naive cells would render them unsafe for clinical and transgenics applications. ICR erasure in primordial germ cells is thought to involve TET protein action [66][67][68][69], and as such, it is not unreasonable to expect that loss of imprinting in naive ESCs could be exacerbated by supplementation of vitamins A and C. This means that in order to strike a balance between imprinting fidelity in naive pluripotent stem cells and the efficiency at which they are derived, fine-tuning of vitamin levels and TET activity may be required …”