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TET1 protein, congenital defects and late-onset diseases
Every mammal starts off as a cluster of cells with the same genetic material. As the embryo develops, this DNA is used to generate the cell-specific building blocks for lungs, the brain, and every other tissue and organ in the body. Research goals are often aimed at determining which genetic information is needed for a specific cell - and when. "When" can be determined by chemical marks or methyl groups added to the DNA at specific positions. Erasing a mark often switches on a specific message, whereas adding a mark usually switches it off. This determines how proteins interpret genetic information.
"The protein prevents the incorrect marking of DNA. We found that the loss of TET1 may lead to severe defects that cause the brain or spinal cord to develop outside the body. The causes of such defects, including spina bifida, are very complex, of course, but our findings suggest that TET1 plays a pivotal role in preventing them."
But incorrect marking of the DNA may also cause late-onset diseases. "This is because TET1 is necessary to control the speed of embryonic development. If the timing for the start of a specific stage is off, the fetus may die. And if it survives, the marks on the DNA may still be improperly erased, possibly leading to mental retardation and cancer later in life."
These findings open up new avenues of research into the origin and prevention of both congenital disorders and various late-onset diseases. The work is published in Nature Genetics.
The mammalian TET enzymes catalyze DNA demethylation. While they have been intensely studied as major epigenetic regulators, little is known about their physiological roles and the extent of functional redundancy following embryo implantation. Here we define non-redundant roles for TET1 at an early postimplantation stage of the mouse embryo, when its paralogs Tet2 and Tet3 are not detectably expressed. TET1 regulates numerous genes defining differentiation programs in the epiblast and extraembryonic ectoderm. In epiblast cells, TET1 demethylates gene promoters via hydroxymethylation and maintains telomere stability. Surprisingly, TET1 represses a majority of epiblast target genes independently of methylation changes, in part through regulation of the gene encoding the transcriptional repressor JMJD8. Dysregulated gene expression in the absence of TET1 causes embryonic defects, which are partially penetrant in an inbred strain but fully lethal in non-inbred mice. Collectively, our study highlights an interplay between the catalytic and non-catalytic activities of TET1 that is essential for normal development.
Other authors: Rita Khoueiry, Abhishek Sohni, Bernard Thienpont, Xinlong Luo, Joris Vande Velde, Michela Bartoccetti, Bram Boeckx, An Zwijsen, Anjana Rao, Diether Lambrechts
Keywords: Epigenetics Stem cells
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