Persistent epigenetic memory impedes rescue of the telomeric phenotype in human ICF iPSCs following DNMT3B correction

  1. Shir Toubiana
  2. Miriam Gagliardi
  3. Mariarosaria Papa
  4. Roberta Manco
  5. Maty Tzukerman
  6. Maria R Matarazzo  Is a corresponding author
  7. Sara Selig  Is a corresponding author
  1. Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion, Israel
  2. ABT CNR, Italy

Abstract

DNA methyltransferase 3B (DNMT3B) is the major DNMT that methylates mammalian genomes during early development. Mutations in human DNMT3B disrupt genome-wide DNA methylation patterns and result in ICF syndrome type 1 (ICF1). To study whether normal DNA methylation patterns may be restored in ICF1 cells, we corrected DNMT3B mutations in induced pluripotent stem cells from ICF1 patients. Focusing on repetitive regions, we show that in contrast to pericentromeric repeats, which reacquire normal methylation, the majority of subtelomeres acquire only partial DNA methylation and, accordingly, the ICF1 telomeric phenotype persists. Subtelomeres resistant to de novo methylation were characterized by abnormally high H3K4 trimethylation (H3K4me3), and short-term reduction of H3K4me3 by pharmacological intervention partially restored subtelomeric DNA methylation. These findings demonstrate that the abnormal epigenetic landscape established in ICF1 cells restricts the recruitment of DNMT3B, and suggest that rescue of epigenetic diseases with genome-wide disruptions will demand further manipulation beyond mutation correction.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE137183 and GSE138265

The following data sets were generated

Article and author information

Author details

  1. Shir Toubiana

    Molecular Medicine Laboratory, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion, Haifa, Israel
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3001-5281
  2. Miriam Gagliardi

    Institute of Genetics and Biophysics, ABT CNR, Naples, Italy
    Competing interests
    The authors declare that no competing interests exist.
  3. Mariarosaria Papa

    Institute of Genetics and Biophysics, ABT CNR, Naples, Italy
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2467-4187
  4. Roberta Manco

    Institute of Genetics and Biophysics, ABT CNR, Naples, Italy
    Competing interests
    The authors declare that no competing interests exist.
  5. Maty Tzukerman

    Molecular Medicine Laboratory, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion, Haifa, Israel
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9080-2511
  6. Maria R Matarazzo

    Institute of Genetics and Biophysics, ABT CNR, Naples, Italy
    For correspondence
    maria.matarazzo@igb.cnr.it
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8192-4322
  7. Sara Selig

    Molecular Medicine Laboratory, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion, Haifa, Israel
    For correspondence
    seligs@technion.ac.il
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5759-9948

Funding

Israel Science Foundation (1362/17)

  • Sara Selig

Epigenomics Flagship Project , Italian Ministry University Research - CNR

  • Maria R Matarazzo

Telethon (GGP15209)

  • Maria R Matarazzo

PON/MISE (2014-2020 FESR F/050011/01-02/X32)

  • Maria R Matarazzo

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Lorenz Studer, Memorial Sloan Kettering Cancer Center, United States

Publication history

  1. Received: April 22, 2019
  2. Accepted: November 17, 2019
  3. Accepted Manuscript published: November 18, 2019 (version 1)
  4. Accepted Manuscript updated: November 20, 2019 (version 2)
  5. Version of Record published: December 6, 2019 (version 3)

Copyright

© 2019, Toubiana et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Shir Toubiana
  2. Miriam Gagliardi
  3. Mariarosaria Papa
  4. Roberta Manco
  5. Maty Tzukerman
  6. Maria R Matarazzo
  7. Sara Selig
(2019)
Persistent epigenetic memory impedes rescue of the telomeric phenotype in human ICF iPSCs following DNMT3B correction
eLife 8:e47859.
https://doi.org/10.7554/eLife.47859

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