Evidence map›Paper›PMID 25822089›Full record

ArticleNature genetics2015

Targeted disruption of DNMT1, DNMT3A and DNMT3B in human embryonic stem cells.

Jing Liao, Rahul Karnik, Hongcang Gu, Michael J Ziller, Kendell Clement, Alexander M Tsankov, Veronika Akopian, Casey A Gifford, Julie Donaghey, Christina Galonska and 8 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 300 papers.

0numbers the graph read from it
0cells of the map it votes in
300citing papers in PubMed
27.4field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

300 citing papers in PubMed, 473 citations in OpenAlex.

  1. Article
  2. Article
  3. Article
  4. Review
  5. Article
  6. Article
  7. Review
  8. Article
  9. Review
  10. Review
  11. Article
  12. Article
  13. Discovery of a Novel DNMT1 Inhibitor with Improved Efficacy in Treating β-Thalassemia.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026
    Article
  14. Article
  15. Article
  16. Article
  17. Article
  18. Article
  19. Article
  20. Epigenetic networks coordinate DNA methylation across the genome.Molecular therapy : the journal of the American Society of Gene Therapy · 2025
    Review

240 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

18 authors at 3 institutions in 1 country.

Jing Liao1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Harvard Stem Cell Institute, Cambridge, Massachusetts, USA. [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Rahul Karnik1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Harvard Stem Cell Institute, Cambridge, Massachusetts, USA. [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.ORCID 000000020400635X
Hongcang GuBroad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Michael J Ziller1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Harvard Stem Cell Institute, Cambridge, Massachusetts, USA. [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Kendell Clement1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Harvard Stem Cell Institute, Cambridge, Massachusetts, USA. [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Alexander M Tsankov1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Harvard Stem Cell Institute, Cambridge, Massachusetts, USA. [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Veronika Akopian1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Harvard Stem Cell Institute, Cambridge, Massachusetts, USA. [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Casey A Gifford1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Harvard Stem Cell Institute, Cambridge, Massachusetts, USA. [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Julie Donaghey1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Harvard Stem Cell Institute, Cambridge, Massachusetts, USA. [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Christina Galonska1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Harvard Stem Cell Institute, Cambridge, Massachusetts, USA. [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Ramona Pop1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Harvard Stem Cell Institute, Cambridge, Massachusetts, USA. [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Deepak ReyonDepartment of Pathology, Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
Shengdar Q TsaiDepartment of Pathology, Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
William Mallard1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Harvard Stem Cell Institute, Cambridge, Massachusetts, USA. [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
J Keith JoungDepartment of Pathology, Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
John L Rinn1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Harvard Stem Cell Institute, Cambridge, Massachusetts, USA. [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Andreas GnirkeBroad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Alexander Meissner1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Harvard Stem Cell Institute, Cambridge, Massachusetts, USA. [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Broad Institute · USMassachusetts General Hospital · USHarvard Stem Cell Institute · US

Funding

Regulatory Roles and Dynamics of Nuclear long-noncoding RNAs in PluripotencyP01GM099117 · NIGMS · HARVARD UNIVERSITY · PI MEISSNER, ALEXANDER · 2011 to 2021
$21.2M
Advancing stem cell technologies using engineered zinc finger proteinsDP1GM105378 · NIGMS · MASSACHUSETTS GENERAL HOSPITAL · PI JOUNG, J. KEITH · 2012 to 2014
$2.6M
Generation and characterization of tools for target-specific de novo DNA methylatR01DA036898 · NIDA · HARVARD UNIVERSITY · PI MEISSNER, ALEXANDER · 2013 to 2017
$1.7M
NCCDPHP CDC HHS DP1 GM105378NIDA NIH HHS R01 DA036898NIGMS NIH HHS DP1 GM105378NIGMS NIH HHS P01 GM099117NIGMS NIH HHS P01GM099117
6 · The paper itself

Abstract

DNA methylation is a key epigenetic modification involved in regulating gene expression and maintaining genomic integrity. Here we inactivated all three catalytically active DNA methyltransferases (DNMTs) in human embryonic stem cells (ESCs) using CRISPR/Cas9 genome editing to further investigate the roles and genomic targets of these enzymes. Disruption of DNMT3A or DNMT3B individually as well as of both enzymes in tandem results in viable, pluripotent cell lines with distinct effects on the DNA methylation landscape, as assessed by whole-genome bisulfite sequencing. Surprisingly, in contrast to findings in mouse, deletion of DNMT1 resulted in rapid cell death in human ESCs. To overcome this immediate lethality, we generated a doxycycline-responsive tTA-DNMT1* rescue line and readily obtained homozygous DNMT1-mutant lines. However, doxycycline-mediated repression of exogenous DNMT1* initiates rapid, global loss of DNA methylation, followed by extensive cell death. Our data provide a comprehensive characterization of DNMT-mutant ESCs, including single-base genome-wide maps of the targets of these enzymes.

Indexed as

DNA MethylationAnimalsApoptosisBase SequenceCatalytic DomainCell DifferentiationCell ProliferationCells, CulturedCell SurvivalCoculture TechniquesCpG IslandsDNA (Cytosine-5-)-Methyltransferase 1DNA (Cytosine-5-)-MethyltransferasesDNA Methyltransferase 3ADNA Methyltransferase 3BEmbryonic Stem CellsDNA (Cytosine-5-)-Methyltransferase 1DNA (Cytosine-5-)-MethyltransferasesDNA Methyltransferase 3ADNA Methyltransferase 3BDNMT1 protein, humanDnmt1 protein, mouseDNMT3A protein, humanDnmt3a protein, mouse

Identifiers

PMID25822089
PMCPMC4414868
OpenAlexW1977463456

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.