The mechanisms surrounding genomic imprinting has always been a bit of black-box, especially when it comes to the erasure of paternal methylation patterns. A recent study led by Yi Zhang at the Boston Children’s Hospital has made a breakthrough in our understanding of imprinting, showing that Tet1 is a major part of the clean-up crew that sanitizes DNA methylation imprints for the next generation.
The Children’s Hospital groups overcame some difficult challenges in their experiments; genomic imprinting is hypersensitive to the environment and very difficult to replicate in vitro. On top of that, maintaining a proper genomic imprinting pattern is an integral part of cellular differentiation and development, with even the slightest abnormality introduced via cultured differences frustrating many a stem cell researcher in the past.
As Zhang points out in their press release, “We’ve long known what proteins are responsible for establishing imprinting patterns, but how erasure occurs has been less clear.” So, guess which active demethylation pathway they looked into first? That’s right, it was Tet. Here’s what the Zhang team found:
- While producing identical genotypes, mating male Tet1 knockouts to wild-type ladies also produced a non-mendelian spectrum of variable phenotypes, like: placental, fetal, and postnatal growth defects, and a touch of early embryonic lethality.
- Genome-wide DNA methylation analysis of embryos and sperm from the Tet1 knock-out mice found DMR hypermethylation in the imprinted genes in sperm.
- RNA-seq data uncovered extensive dysregulation of imprinted genes in the children, caused by paternal loss of Tet1 function.
- A good chunk of the defects were the result of dysregulated imprinted genes (like Peg10 and Peg3) with aberrant hypermethylation in the paternal allele of differentially methylated regions (DMRs).
The researchers conclude from their work that Tet1 functions to wipe out remaining methylation, including imprinted genes, at the late reprogramming stage, and also erases paternal imprints in the female germ line. Zhang also shared that in the future “understanding how imprints are erased could lead to more effective methods of high-quality iPS cell generation”.
Make sure your DNA methylation imprints will pass inspection over at Nature, December 2013