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강진석Jinsuk Kang

La Jolla Institute for Allergy and Immunology

Proc. Natl. Acad. Sci. USA, August 4, 2015 vol. 112 no. 31 E4236-E4245. Published online before print July 21, 2015 | doi: 10.1073/pnas.1510510112 Simultaneous deletion of the methylcytosine oxidases Tet1 and Tet3 increases transcriptome variability in early embryogenesis

Abstract

Jinsuk Kang^a, Matthias Lienhard^a,b, William A. Pastor^a,1, Ashu Chawla^a, Mark Novotny^c, Ageliki Tsagaratou^a, Roger S. Lasken^c, Elizabeth C. Thompson^a,2, M. Azim Surani^d, Sergei B. Koralov^e, Sundeep Kalantry^f, Lukas Chavez^a,3,4, and Anjana Rao^a,g,h,i,4

^aDivision of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, CA 92037;

^bMax Planck Institute for Molecular Genetics, 14195 Berlin, Germany;

^cJ. Craig Venter Institute, La Jolla, CA 92037;

^dWellcome Trust Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, United Kingdom;

^eDepartment of Pathology, New York University School of Medicine, New York, NY 10016;

^fDepartment of Human Genetics, University of Michigan, Ann Arbor, MI 48109;

^gDepartment of Pharmacology, University of California at San Diego, La Jolla, CA 92093;

^hMoores Cancer Center, University of California at San Diego, La Jolla, CA 92093;

ⁱSanford Consortium for Regenerative Medicine, La Jolla, CA 92037

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.

DNA methylation, cholesterol biosynthesis, TET methylcytosine oxidases, 5-hydroxymethylcytosine, 5hmC

¹Present address: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095.

²Present address: Immunity, Cell Press, Cambridge, MA 02139.

³Present address: Division of Pediatric Neurooncology, Group Leader Computational Oncoepigenomics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.

⁴To whom correspondence may be addressed.

Author contributions: J.K., M.A.S., S.K., and A.R. designed research; J.K. performed research; J.K., W.A.P., M.N., A.T., R.S.L., E.C.T., and S.B.K. contributed new reagents/analytic tools; J.K., M.L., A.C., and L.C. analyzed data; and J.K. and A.R. wrote the paper.

논문정보

형식Research article
게재일2015년 07월 (BRIC 등록일 2015-08-05)
연구진국외 연구진
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