TET proteins safeguard bivalent promoters from de novo methylation in human embryonic stem cells Journal Article

Authors: Verma, N.; Pan, H.; Doré, L. C.; Shukla, A.; Li, Q. V.; Pelham-Webb, B.; Teijeiro, V.; González, F.; Krivtsov, A.; Chang, C. J.; Papapetrou, E. P.; He, C.; Elemento, O.; Huangfu, D.
Article Title: TET proteins safeguard bivalent promoters from de novo methylation in human embryonic stem cells
Abstract: TET enzymes oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which can lead to DNA demethylation. However, direct connections between TET-mediated DNA demethylation and transcriptional output are difficult to establish owing to challenges in distinguishing global versus locus-specific effects. Here we show that TET1, TET2 and TET3 triple-knockout (TKO) human embryonic stem cells (hESCs) exhibit prominent bivalent promoter hypermethylation without an overall corresponding decrease in gene expression in the undifferentiated state. Focusing on the bivalent PAX6 locus, we find that increased DNMT3B binding is associated with promoter hypermethylation, which precipitates a neural differentiation defect and failure of PAX6 induction during differentiation. dCas9-mediated locus-specific demethylation and global inactivation of DNMT3B in TKO hESCs partially reverses the hypermethylation at the PAX6 promoter and improves differentiation to neuroectoderm. Taking these findings together with further genome-wide methylation and TET1 and DNMT3B ChIP-seq analyses, we conclude that TET proteins safeguard bivalent promoters from de novo methylation to ensure robust lineage-specific transcription upon differentiation. © 2017 The Author(s).
Keywords: controlled study; human cell; promoter region; protein function; gene; gene expression; protein binding; gene locus; cell differentiation; dna methylation; enzyme inactivation; protein induction; transcription factor pax6; dna methyltransferase 1; dna methyltransferase 3b; tet2 gene; enzyme active site; dna methyltransferase 3a; neuroectoderm; human; priority journal; article; tet3 gene; de novo methylation; human embryonic stem cell; tet gene; tet1 gene
Journal Title: Nature Genetics
Volume: 50
ISSN: 1061-4036
Publisher: Nature Publishing Group  
Date Published: 2018-01-01
Start Page: 83
End Page: 95
Language: English
DOI: 10.1038/s41588-017-0002-y
PROVIDER: scopus
PMCID: PMC5742051
PUBMED: 29203910
Notes: Article -- Export Date: 6 February 2018 -- Source: Scopus
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MSK Authors
  1. Danwei Huangfu
    28 Huangfu
  2. Qing Li
    6 Li
  3. Nipun Verma
    9 Verma
  4. Abhijit Shukla
    2 Shukla