1. Developmental Biology
  2. Genetics and Genomics

In vivo targeting of de novo DNA methylation by histone modifications in yeast and mouse

  1. Marco Morselli  Is a corresponding author
  2. William A Pastor
  3. Barbara Montanini
  4. Kevin Nee
  5. Roberto Ferrari
  6. Kai Fu
  7. Giancarlo Bonora
  8. Liudmilla Rubbi
  9. Amander T Clark
  10. Simone Ottonello
  11. Steven E Jacobsen
  12. Matteo Pellegrini
  1. University of California, Los Angeles, United States
  2. Laboratory of Functional Genomics and Protein Engineering, Italy
https://doi.org/10.7554/eLife.06205
Share this article
Cite this article
  1. Marco Morselli
  2. William A Pastor
  3. Barbara Montanini
  4. Kevin Nee
  5. Roberto Ferrari
  6. Kai Fu
  7. Giancarlo Bonora
  8. Liudmilla Rubbi
  9. Amander T Clark
  10. Simone Ottonello
  11. Steven E Jacobsen
  12. Matteo Pellegrini
(2015)
In vivo targeting of de novo DNA methylation by histone modifications in yeast and mouse
eLife 4:e06205.
https://doi.org/10.7554/eLife.06205
  2. Download BibTeX
  3. Download .RIS

Abstract

Methylation of cytosines (5meC) is a widespread heritable DNA modification. During mammalian development, two global demethylation events are followed by waves of de novo DNA methylation. In vivo mechanisms of DNA methylation establishment are largely uncharacterized. Here we use Saccharomyces cerevisiae as a system lacking DNA methylation to define the chromatin features influencing the activity of the murine DNMT3B. Our data demonstrate that DNMT3B and H3K4 methylation are mutually exclusive and that DNMT3B is co-localized with H3K36 methylated regions. In support of this observation, DNA methylation analysis in yeast strains without Set1 and Set2 show an increase of relative 5meC levels at the TSS and a decrease in the gene-body, respectively. We extend our observation to the murine male germline, where H3K4me3 is strongly anti-correlated while H3K36me3 correlates with accelerated DNA methylation. These results show the importance of H3K36 methylation for gene-body DNA methylation in vivo.

Article and author information

Author details

  1. Marco Morselli

    Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
    For correspondence
    mmorselli@ucla.edu
    Competing interests
    The authors declare that no competing interests exist.

  2. William A Pastor

    Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Barbara Montanini

    Biochemistry and Molecular Biology Unit, Department of Life Sciences, Laboratory of Functional Genomics and Protein Engineering, Parma, Italy
    Competing interests
    The authors declare that no competing interests exist.

  4. Kevin Nee

    Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Roberto Ferrari

    Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Kai Fu

    Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Giancarlo Bonora

    Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Liudmilla Rubbi

    Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Amander T Clark

    Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Simone Ottonello

    Biochemistry and Molecular Biology Unit, Department of Life Sciences, Laboratory of Functional Genomics and Protein Engineering, Parma, Italy
    Competing interests
    The authors declare that no competing interests exist.

  11. Steven E Jacobsen

    Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

  12. Matteo Pellegrini

    Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Bing Ren, University of California, San Diego School of Medicine, United States

Ethics

Animal experimentation: All animal experimentation was conducted with the highest ethical standards in accordance with UCLA policy and procedures (DHHS OLAW A3196-01, AAALAC #000408 and protocol # 2008-070), and applicable provisions of the USDA Animal Welfare Act Regulations, the Public Health Service Policy on Humane Care and Use of Laboratory Animals, and the Guide for the Care and Use of Laboratory Animals.

Version history

  1. Received: December 20, 2014
  2. Accepted: April 2, 2015
  3. Accepted Manuscript published: April 7, 2015 (version 1)
  4. Accepted Manuscript updated: April 8, 2015 (version 2)
  5. Version of Record published: April 29, 2015 (version 3)
  6. Version of Record updated: August 31, 2017 (version 4)

Copyright

© 2015, Morselli 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.

Metrics

  • 7,144
    views
  • 1,430
    downloads
  • 137
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Marco Morselli
  2. William A Pastor
  3. Barbara Montanini
  4. Kevin Nee
  5. Roberto Ferrari
  6. Kai Fu
  7. Giancarlo Bonora
  8. Liudmilla Rubbi
  9. Amander T Clark
  10. Simone Ottonello
  11. Steven E Jacobsen
  12. Matteo Pellegrini
(2015)
In vivo targeting of de novo DNA methylation by histone modifications in yeast and mouse
eLife 4:e06205.
https://doi.org/10.7554/eLife.06205

Share this article

https://doi.org/10.7554/eLife.06205

Categories and tags

Research organisms

Further reading

    1. Developmental Biology
    2. Physics of Living Systems

    Morphogenesis: The enigma of cell intercalation

    Raphaël Clément
    Insight

    Geometric criteria can be used to assess whether cell intercalation is active or passive during the convergent extension of tissue.

    1. Computational and Systems Biology
    2. Developmental Biology

    The MODY-associated KCNK16 L114P mutation increases islet glucagon secretion and limits insulin secretion resulting in transient neonatal diabetes and glucose dyshomeostasis in adults

    Arya Y Nakhe, Prasanna K Dadi ... David A Jacobson
    Research Article

    The gain-of-function mutation in the TALK-1 K+ channel (p.L114P) is associated with maturity-onset diabetes of the young (MODY). TALK-1 is a key regulator of β-cell electrical activity and glucose-stimulated insulin secretion. The KCNK16 gene encoding TALK-1 is the most abundant and β-cell-restricted K+ channel transcript. To investigate the impact of KCNK16 L114P on glucose homeostasis and confirm its association with MODY, a mouse model containing the Kcnk16 L114P mutation was generated. Heterozygous and homozygous Kcnk16 L114P mice exhibit increased neonatal lethality in the C57BL/6J and the CD-1 (ICR) genetic background, respectively. Lethality is likely a result of severe hyperglycemia observed in the homozygous Kcnk16 L114P neonates due to lack of glucose-stimulated insulin secretion and can be reduced with insulin treatment. Kcnk16 L114P increased whole-cell β-cell K+ currents resulting in blunted glucose-stimulated Ca2+ entry and loss of glucose-induced Ca2+ oscillations. Thus, adult Kcnk16 L114P mice have reduced glucose-stimulated insulin secretion and plasma insulin levels, which significantly impairs glucose homeostasis. Taken together, this study shows that the MODY-associated Kcnk16 L114P mutation disrupts glucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by inhibiting islet insulin secretion during development. These data suggest that TALK-1 is an islet-restricted target for the treatment for diabetes.