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Genome Biol. 2018 Jul 12;19(1):88. doi: 10.1186/s13059-018-1464-7.

DNMT3A and TET1 cooperate to regulate promoter epigenetic landscapes in mouse embryonic stem cells.

Gu T1, Lin X2,3,4,5, Cullen SM1,6,7, Luo M1, Jeong M1, Estecio M8, Shen J8, Hardikar S8, Sun D2,3,9, Su J2,3, Rux D10, Guzman A1, Lee M9, Qi LS5, Chen JJ11, Kyba M10, Huang Y9, Chen T8, Li W12,13, Goodell MA14,15.

Author information

1
Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, 77030, USA.
2
Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.
3
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
4
Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, Shanghai, China.
5
Department of Bioengineering, Stanford University, Stanford, California, USA.
6
Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
7
Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, 77030, USA.
8
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, 78957, USA.
9
Center for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, 77030, USA.
10
Lillehei Heart Institute and Department of Pediatrics, University of Minnesota, Minneapolis, MN, 55455, USA.
11
Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China.
12
Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA. wl1@bcm.edu.
13
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. wl1@bcm.edu.
14
Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, 77030, USA. goodell@bcm.edu.
15
Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA. goodell@bcm.edu.

Abstract

BACKGROUND:

DNA methylation is a heritable epigenetic mark, enabling stable but reversible gene repression. In mammalian cells, DNA methyltransferases (DNMTs) are responsible for modifying cytosine to 5-methylcytosine (5mC), which can be further oxidized by the TET dioxygenases to ultimately cause DNA demethylation. However, the genome-wide cooperation and functions of these two families of proteins, especially at large under-methylated regions, called canyons, remain largely unknown.

RESULTS:

Here we demonstrate that DNMT3A and TET1 function in a complementary and competitive manner in mouse embryonic stem cells to mediate proper epigenetic landscapes and gene expression. The longer isoform of DNMT3A, DNMT3A1, exhibits significant enrichment at distal promoters and canyon edges, but is excluded from proximal promoters and canyons where TET1 shows prominent binding. Deletion of Tet1 increases DNMT3A1 binding capacity at and around genes with wild-type TET1 binding. However, deletion of Dnmt3a has a minor effect on TET1 binding on chromatin, indicating that TET1 may limit DNA methylation partially by protecting its targets from DNMT3A and establishing boundaries for DNA methylation. Local CpG density may determine their complementary binding patterns and therefore that the methylation landscape is encoded in the DNA sequence. Furthermore, DNMT3A and TET1 impact histone modifications which in turn regulate gene expression. In particular, they regulate Polycomb Repressive Complex 2 (PRC2)-mediated H3K27me3 enrichment to constrain gene expression from bivalent promoters.

CONCLUSIONS:

We conclude that DNMT3A and TET1 regulate the epigenome and gene expression at specific targets via their functional interplay.

KEYWORDS:

DNA methylation; DNMT3A; Embryonic stem cells; H3K27me3; PRC2; TET1

PMID:
30001199
PMCID:
PMC6042404
DOI:
10.1186/s13059-018-1464-7
[Indexed for MEDLINE]
Free PMC Article

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