MeCP2 nuclear dynamics in live neurons results from low and high affinity chromatin interactions

  1. Francesco M Piccolo  Is a corresponding author
  2. Zhe Liu
  3. Peng Dong
  4. Ching-Lung Hsu
  5. Elitsa I Stoyanova
  6. Anjana Rao
  7. Robert Tjian
  8. Nathaniel Heintz  Is a corresponding author
  1. Howard Hughes Medical Institute, The Rockefeller University, United States
  2. Janelia Research Campus, Howard Hughes Medical Institute, United States
  3. La Jolla Institute For Allergy and Immunology, United States
  4. Howard Hughes Medical Institute, University of California, Berkeley, United States

Abstract

Methyl-CpG-binding-Protein 2 (MeCP2) is an abundant nuclear protein highly enriched in neurons. Here we report live-cell single-molecule imaging studies of the kinetic features of mouse MeCP2 at high spatial-temporal resolution. MeCP2 displays dynamic features that are distinct from both highly mobile transcription factors and immobile histones. Stable binding of MeCP2 in living neurons requires its methyl-binding domain and is sensitive to DNA modification levels. Diffusion of unbound MeCP2 is strongly constrained by weak, transient interactions mediated primarily by its AT-hook domains, and varies with the level of chromatin compaction and cell type. These findings extend previous studies of the role of the MeCP2 MBD in high affinity DNA binding to living neurons, and identify a new role for its AT-hooks domains as critical determinants of its kinetic behavior. They suggest that limited nuclear diffusion of MeCP2 in live neurons contributes to its local impact on chromatin structure and gene expression.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Francesco M Piccolo

    Laboratory of Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
    For correspondence
    fpiccolo@rockefeller.edu
    Competing interests
    No competing interests declared.
  2. Zhe Liu

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3592-3150
  3. Peng Dong

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    No competing interests declared.
  4. Ching-Lung Hsu

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    No competing interests declared.
  5. Elitsa I Stoyanova

    Laboratory of Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6400-6119
  6. Anjana Rao

    Division of Signaling and Gene Expression, La Jolla Institute For Allergy and Immunology, La Jolla, United States
    Competing interests
    No competing interests declared.
  7. Robert Tjian

    Department of Molecular and Cell Biology, Li Ka Shing Center for Biomedical and Health Sciences, CIRM Center of Excellence, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States
    Competing interests
    Robert Tjian, One of the three founding funders of eLife and a member of eLife's Board of Directors.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0539-8217
  8. Nathaniel Heintz

    Laboratory of Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
    For correspondence
    heintz@rockefeller.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8874-8704

Funding

Howard Hughes Medical Institute

  • Nathaniel Heintz

Howard Hughes Medical Institute

  • Zhe Liu

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

Reviewing Editor

  1. Job Dekker, University of Massachusetts Medical School, United States

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (# 16944) of the Rockefeller University. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Rockefeller University (OLAW assurance # #A3081-01).

Version history

  1. Received: August 28, 2019
  2. Accepted: December 22, 2019
  3. Accepted Manuscript published: December 23, 2019 (version 1)
  4. Version of Record published: January 13, 2020 (version 2)

Copyright

© 2019, Piccolo 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. Francesco M Piccolo
  2. Zhe Liu
  3. Peng Dong
  4. Ching-Lung Hsu
  5. Elitsa I Stoyanova
  6. Anjana Rao
  7. Robert Tjian
  8. Nathaniel Heintz
(2019)
MeCP2 nuclear dynamics in live neurons results from low and high affinity chromatin interactions
eLife 8:e51449.
https://doi.org/10.7554/eLife.51449

Share this article

https://doi.org/10.7554/eLife.51449

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