In vivo analysis reveals that ATP-hydrolysis couples remodeling to SWI/SNF release from chromatin

  1. Ben Tilly  Is a corresponding author
  2. Gillian Chalkley
  3. Jan van der Knaap
  4. Yuri Moshkin
  5. Tsung Wai Kan
  6. Dick HW Dekkers
  7. Jeroen Demmers
  8. Peter Verrijzer  Is a corresponding author
  1. Erasmus University Medical Center, Netherlands
  2. Erasmus MC, Netherlands
  3. ErasmusMC, Netherlands

Abstract

ATP-dependent chromatin remodelers control the accessibility of genomic DNA through nucleosome mobilization. However, the dynamics of genome exploration by remodelers, and the role of ATP hydrolysis in this process remain unclear. We used live-cell imaging of Drosophila polytene nuclei to monitor Brahma (BRM) remodeler interactions with its chromosomal targets. In parallel, we measured local chromatin condensation and its effect on BRM association. Surprisingly, only a small portion of BRM is bound to chromatin at any given time. BRM binds decondensed chromatin but is excluded from condensed chromatin, limiting its genomic search space. BRM-chromatin interactions are highly dynamic, whereas histone-exchange is limited and much slower. Intriguingly, loss of ATP hydrolysis enhanced chromatin retention and clustering of BRM, which was associated with reduced histone turnover. Thus, ATP hydrolysis couples nucleosome remodeling to remodeler release, driving a continuous transient probing of the genome.

Data availability

The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (www.proteomexchange.org) via the PRIDE partner repository with the dataset identifier PXD025474.All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 2 and Figure 2-figure-supplement1

The following data sets were generated

Article and author information

Author details

  1. Ben Tilly

    Biochemistry, Erasmus University Medical Center, Rotterdam, Netherlands
    For correspondence
    b.tilly@erasmusmc.nl
    Competing interests
    The authors declare that no competing interests exist.
  2. Gillian Chalkley

    Biochemistry, Erasmus University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  3. Jan van der Knaap

    Biochemistry, Erasmus University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  4. Yuri Moshkin

    Biochemistry, Erasmus University Medical Center, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  5. Tsung Wai Kan

    Biochemistry, Erasmus MC, 3015 CN Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  6. Dick HW Dekkers

    Proteomics Center, ErasmusMC, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  7. Jeroen Demmers

    Proteomics Center, ErasmusMC, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  8. Peter Verrijzer

    Biochemistry, Erasmus University Medical Center, Rotterdam, Netherlands
    For correspondence
    c.verrijzer@erasmusmc.nl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6476-3264

Funding

FOM-AMOLF (DNA at Work)

  • Peter Verrijzer

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

Reviewing Editor

  1. Sebastian Deindl, Uppsala University, Sweden

Version history

  1. Received: April 14, 2021
  2. Preprint posted: April 23, 2021 (view preprint)
  3. Accepted: July 26, 2021
  4. Accepted Manuscript published: July 27, 2021 (version 1)
  5. Version of Record published: August 9, 2021 (version 2)

Copyright

© 2021, Tilly 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

  • 1,492
    Page views
  • 254
    Downloads
  • 11
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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. Ben Tilly
  2. Gillian Chalkley
  3. Jan van der Knaap
  4. Yuri Moshkin
  5. Tsung Wai Kan
  6. Dick HW Dekkers
  7. Jeroen Demmers
  8. Peter Verrijzer
(2021)
In vivo analysis reveals that ATP-hydrolysis couples remodeling to SWI/SNF release from chromatin
eLife 10:e69424.
https://doi.org/10.7554/eLife.69424

Share this article

https://doi.org/10.7554/eLife.69424

Further reading

    1. Biochemistry and Chemical Biology
    2. Cell Biology
    Chenjie Xia, Huihui Xu ... Hongting Jin
    Research Article

    Glucocorticoid-induced osteonecrosis of the femoral head (GONFH) is a common refractory joint disease characterized by bone damage and the collapse of femoral head structure. However, the exact pathological mechanisms of GONFH remain unknown. Here, we observed abnormal osteogenesis and adipogenesis associated with decreased β-catenin in the necrotic femoral head of GONFH patients. In vivo and in vitro studies further revealed that glucocorticoid exposure disrupted osteogenic/adipogenic differentiation of bone marrow mesenchymal cells (BMSCs) by inhibiting β-catenin signaling in glucocorticoid-induced GONFH rats. Col2+ lineage largely contributes to BMSCs and was found an osteogenic commitment in the femoral head through 9 mo of lineage trace. Specific deletion of β-catenin gene (Ctnnb1) in Col2+ cells shifted their commitment from osteoblasts to adipocytes, leading to a full spectrum of disease phenotype of GONFH in adult mice. Overall, we uncover that β-catenin inhibition disrupting the homeostasis of osteogenic/adipogenic differentiation contributes to the development of GONFH and identify an ideal genetic-modified mouse model of GONFH.

    1. Biochemistry and Chemical Biology
    2. Plant Biology
    Pradeep Kumar, Ankit Roy ... Rajan Sankaranarayanan
    Research Article

    Aldehydes, being an integral part of carbon metabolism, energy generation, and signalling pathways, are ingrained in plant physiology. Land plants have developed intricate metabolic pathways which involve production of reactive aldehydes and its detoxification to survive harsh terrestrial environments. Here, we show that physiologically produced aldehydes, i.e., formaldehyde and methylglyoxal in addition to acetaldehyde, generate adducts with aminoacyl-tRNAs, a substrate for protein synthesis. Plants are unique in possessing two distinct chiral proofreading systems, D-aminoacyl-tRNA deacylase1 (DTD1) and DTD2, of bacterial and archaeal origins, respectively. Extensive biochemical analysis revealed that only archaeal DTD2 can remove the stable D-aminoacyl adducts on tRNA thereby shielding archaea and plants from these system-generated aldehydes. Using Arabidopsis as a model system, we have shown that the loss of DTD2 gene renders plants susceptible to these toxic aldehydes as they generate stable alkyl modification on D-aminoacyl-tRNAs, which are recycled only by DTD2. Bioinformatic analysis identifies the expansion of aldehyde metabolising repertoire in land plant ancestors which strongly correlates with the recruitment of archaeal DTD2. Finally, we demonstrate that the overexpression of DTD2 offers better protection against aldehydes than in wild type Arabidopsis highlighting its role as a multi-aldehyde detoxifier that can be explored as a transgenic crop development strategy.