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Simultaneous deletion of the methylcytosine oxidases Tet1 and Tet3 increases transcriptome variability in early embryogenesis.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2015 Aug 04; Vol. 112 (31), pp. E4236-45. Date of Electronic Publication: 2015 Jul 21. - Publication Year :
- 2015
-
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.
- Subjects :
- Animals
Biomarkers metabolism
Blastocyst metabolism
Blastomeres metabolism
Blastomeres pathology
Cell Lineage
Cholesterol biosynthesis
DNA metabolism
DNA-Binding Proteins deficiency
DNA-Binding Proteins genetics
Dioxygenases
Down-Regulation genetics
Embryo Loss metabolism
Embryo Loss pathology
Embryo, Mammalian pathology
Genomic Imprinting
Hedgehog Proteins metabolism
Mice, Inbred C57BL
Mice, Knockout
Proto-Oncogene Proteins deficiency
Proto-Oncogene Proteins genetics
Repetitive Sequences, Nucleic Acid genetics
Sequence Analysis, RNA
Signal Transduction genetics
5-Methylcytosine metabolism
DNA-Binding Proteins metabolism
Embryonic Development genetics
Gene Deletion
Gene Expression Regulation, Developmental
Proto-Oncogene Proteins metabolism
Transcriptome genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 112
- Issue :
- 31
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 26199412
- Full Text :
- https://doi.org/10.1073/pnas.1510510112