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000126813 0247_ $$2doi$$a10.1073/pnas.1510510112
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000126813 1001_ $$aKang, Jinsuk$$b0
000126813 245__ $$aSimultaneous deletion of the methylcytosine oxidases Tet1 and Tet3 increases transcriptome variability in early embryogenesis.
000126813 260__ $$aWashington, DC$$bNational Acad. of Sciences$$c2015
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000126813 520__ $$aDioxygenases of the TET (Ten-Eleven Translocation) family produce oxidized methylcytosines, intermediates in DNA demethylation, as well as new epigenetic marks. Here we show data suggesting that TET proteins maintain the consistency of gene transcription. Embryos lacking Tet1 and Tet3 (Tet1/3 DKO) displayed a strong loss of 5-hydroxymethylcytosine (5hmC) and a concurrent increase in 5-methylcytosine (5mC) at the eight-cell stage. Single cells from eight-cell embryos and individual embryonic day 3.5 blastocysts showed unexpectedly variable gene expression compared with controls, and this variability correlated in blastocysts with variably increased 5mC/5hmC in gene bodies and repetitive elements. Despite the variability, genes encoding regulators of cholesterol biosynthesis were reproducibly down-regulated in Tet1/3 DKO blastocysts, resulting in a characteristic phenotype of holoprosencephaly in the few embryos that survived to later stages. Thus, TET enzymes and DNA cytosine modifications could directly or indirectly modulate transcriptional noise, resulting in the selective susceptibility of certain intracellular pathways to regulation by TET proteins.
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000126813 650_7 $$2NLM Chemicals$$aBiomarkers
000126813 650_7 $$2NLM Chemicals$$aDNA-Binding Proteins
000126813 650_7 $$2NLM Chemicals$$aHedgehog Proteins
000126813 650_7 $$2NLM Chemicals$$aProto-Oncogene Proteins
000126813 650_7 $$2NLM Chemicals$$aShh protein, mouse
000126813 650_7 $$2NLM Chemicals$$aTET1 protein, mouse
000126813 650_7 $$2NLM Chemicals$$aTet3 protein, mouse
000126813 650_7 $$06R795CQT4H$$2NLM Chemicals$$a5-Methylcytosine
000126813 650_7 $$09007-49-2$$2NLM Chemicals$$aDNA
000126813 650_7 $$097C5T2UQ7J$$2NLM Chemicals$$aCholesterol
000126813 7001_ $$aLienhard, Matthias$$b1
000126813 7001_ $$aPastor, William A$$b2
000126813 7001_ $$aChawla, Ashu$$b3
000126813 7001_ $$aNovotny, Mark$$b4
000126813 7001_ $$aTsagaratou, Ageliki$$b5
000126813 7001_ $$aLasken, Roger S$$b6
000126813 7001_ $$aThompson, Elizabeth C$$b7
000126813 7001_ $$aSurani, M Azim$$b8
000126813 7001_ $$aKoralov, Sergei B$$b9
000126813 7001_ $$aKalantry, Sundeep$$b10
000126813 7001_ $$0P:(DE-He78)082dd3179733e3e716a58eb90f418a78$$aChavez, Lukas$$b11$$udkfz
000126813 7001_ $$aRao, Anjana$$b12
000126813 773__ $$0PERI:(DE-600)1461794-8$$a10.1073/pnas.1510510112$$gVol. 112, no. 31, p. E4236 - E4245$$n31$$pE4236 - E4245$$tProceedings of the National Academy of Sciences of the United States of America$$v112$$x1091-6490$$y2015
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