Simultaneous deletion of the methylcytosine oxidases Tet1 and Tet3 increases transcriptome variability in early embryogenesis
Year: 2015
Type: article
Abstract: 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.
Institutions: La Jolla Institute for Immunology, Max Planck Institute for Molecular Genetics, J. Craig Venter Institute, University of Cambridge, The Gurdon Institute, NYU Langone Health, New York University, University of Michigan, University of California San Diego, Sanford Consortium for Regenerative Medicine, Moores Cancer Center
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Funders: Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Wellcome Trust, National Institutes of Health, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, Office of Strategic Coordination, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G120413199, Initiation of Epigenetic Transcriptional Regulation, Role of TET Proteins in ES Cell Pluripotency and Function, G5515063844, G5609553189, Illumina HiSeq 2500 Sequencing System, Regulated Accessibility of a cytokine gene locus., G7976538385, Core support for the Wellcome Trust Cancer Research UK Gurdon Institute., Epigenetic Mechanisms of X-chromosome Inactivation, G8764524762
OpenAlex ID: W2152478160