Simultaneous deletion of the methylcytosine oxidases Tet1 and Tet3 increases transcriptome variability in early embryogenesis.
Pastor, William A
Lasken, Roger S
Thompson, Elizabeth C
Koralov, Sergei B
Simultaneous deletion of Tet1 and Tet3 increases transcriptome variability in early embryogenesis
National Academy of Sciences
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Kang, J., Lienhard, M., Pastor, W. A., Chawla, A., Novotny, M., Tsagaratou, A., Lasken, R. S., et al. (2015). Simultaneous deletion of the methylcytosine oxidases Tet1 and Tet3 increases transcriptome variability in early embryogenesis.. PNAS, 112 E4236-E4245. https://doi.org/10.1073/pnas.1510510112
Dioxygenases of the TET (Ten-Eleven Translocation) family produce oxidized methylcytosines, intermediates in DNA demethylation, as well as new epigenetic marks. Here we show data suggesting that TET proteins maintain the consistency of gene transcription. Embryos lacking Tet1 and Tet3 (Tet1/3 DKO) displayed a strong loss of 5-hydroxymethylcytosine (5hmC) and a concurrent increase in 5-methylcytosine (5mC) at the eight-cell stage. Single cells from eight-cell embryos and individual embryonic day 3.5 blastocysts showed unexpectedly variable gene expression compared with controls, and this variability correlated in blastocysts with variably increased 5mC/5hmC in gene bodies and repetitive elements. Despite the variability, genes encoding regulators of cholesterol biosynthesis were reproducibly down-regulated in Tet1/3 DKO blastocysts, resulting in a characteristic phenotype of holoprosencephaly in the few embryos that survived to later stages. Thus, TET enzymes and DNA cytosine modifications could directly or indirectly modulate transcriptional noise, resulting in the selective susceptibility of certain intracellular pathways to regulation by TET proteins.
5-hydroxymethylcytosine, 5hmC, DNA methylation, TET methylcytosine oxidases, cholesterol biosynthesis
J.K. was supported by a postdoctoral fellowship from the Jane Coffin Childs Memorial Fund for Medical Research. W.A.P. was supported by the National Science Foundation predoctoral graduate research fellowship while this work was being performed, and subsequently by a postdoctoral fellowship from the Jane Coffin Childs Memorial Fund for Medical Research. L.C. was the recipient of a Feodor-Lynen fellowship from the Alexander von Humboldt foundation. M.L. is supported by the Max Planck Society within its International Max Planck Research School for Computational Biology and Scientific Computing program (IMPRS-CBSC). A.T. was the recipient of an Irvington postdoctoral fellowship from the Cancer Research Institute. This work was supported by NIH R01 Grants AI044432 and HD065812 (to A.R.) and a Director’s New Innovator Award (DP2-OD-008646-01) (to S.K.).
External DOI: https://doi.org/10.1073/pnas.1510510112
This record's URL: https://www.repository.cam.ac.uk/handle/1810/250574