Exploring chromosomal structural heterogeneity across multiple cell lines

  1. Ryan R Cheng  Is a corresponding author
  2. Vinicius Contessoto
  3. Erez Lieberman-Aiden
  4. Peter G Wolynes
  5. Michele Di Pierro  Is a corresponding author
  6. Jose N Onuchic  Is a corresponding author
  1. Rice University, United States
  2. Brazilian Center for Research in Energy and Materials, Brazil
  3. Baylor College of Medicine, United States
  4. Northeastern University, United States

Abstract

Using computer simulations, we generate cell-specific 3D chromosomal structures and compare them to recently published chromatin structures obtained through microscopy. We demonstrate using machine learning and polymer physics simulations that epigenetic information can be used to predict the structural ensembles of multiple human cell lines. Theory predicts that chromosome structures are fluid and can only be described by an ensemble, which is consistent with the observation that chromosomes exhibit no unique fold. Nevertheless, our analysis of both structures from simulation and microscopy reveals that short segments of chromatin make two-state transitions between closed conformations and open dumbbell conformations. Finally, we study the conformational changes associated with the switching of genomic compartments observed in human cell lines. The formation of genomic compartments resembles hydrophobic collapse in protein folding, with the aggregation of denser and predominantly inactive chromatin driving the positioning of active chromatin toward the surface of individual chromosomal territories.

Data availability

All of the simulated chromosome structures have been deposited in the Nucleome Data Bank (https://ndb.rice.edu/Data).

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Ryan R Cheng

    Center for Theoretical Biological Physics, Rice University, Houston, United States
    For correspondence
    ryan.r.cheng@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6378-295X
  2. Vinicius Contessoto

    Brazilian Biorenewables National Laboratory, Brazilian Center for Research in Energy and Materials, Campinas, Brazil
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1891-9563
  3. Erez Lieberman-Aiden

    Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Peter G Wolynes

    Center for Theoretical Biological Physics, Rice University, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Michele Di Pierro

    Department of Physics, Northeastern University, Boston, United States
    For correspondence
    m.dipierro@northeastern.edu
    Competing interests
    The authors declare that no competing interests exist.
  6. Jose N Onuchic

    Center for Theoretical Biological Physics and Department of Physics, Rice University, Houston, United States
    For correspondence
    jonuchic@rice.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9448-0388

Funding

National Science Foundation (PHY-1427654)

  • Ryan R Cheng
  • Vinicius Contessoto
  • Erez Lieberman-Aiden
  • Peter G Wolynes
  • Michele Di Pierro
  • Jose N Onuchic

NHGRI Center for Excellence for Genomic Sciences (HG006193)

  • Erez Lieberman-Aiden

Welch Foundation (Q-1866)

  • Erez Lieberman-Aiden

Cancer Prevention and Research Institute of Texas (R1304)

  • Erez Lieberman-Aiden

NIH Office of the Director (U01HL130010)

  • Erez Lieberman-Aiden

NIH Office of the Director (UM1HG009375)

  • Erez Lieberman-Aiden

NVIDIA Research Center Award

  • Erez Lieberman-Aiden

IBM University Challenge Award

  • Erez Lieberman-Aiden

Google Research Award

  • Erez Lieberman-Aiden

McNair Medical Institute Scholar

  • Erez Lieberman-Aiden

President's Early Career in Science and Engineering

  • Erez Lieberman-Aiden

National Science Foundation (CHE-1614101)

  • Jose N Onuchic

Welch Foundation (C-1792)

  • Jose N Onuchic

Cancer Prevention and Research Institute of Texas

  • Jose N Onuchic

Welch Foundation

  • Vinicius Contessoto

Sao Paulo Research Foundation and Higher Education Personnel (2016/13998-8)

  • Vinicius Contessoto

Higher Education Personnel Improvement Coordination (2017/09662-7)

  • Vinicius Contessoto

D. R. Bullard-Welch Chair at Rice University (Grant C-0016)

  • Peter G Wolynes

NIH Office of the Director (1DP2OD008540-01)

  • Erez Lieberman-Aiden

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

Reviewing Editor

  1. Yibing Shan, DE Shaw Research, United States

Version history

  1. Received: June 22, 2020
  2. Accepted: October 8, 2020
  3. Accepted Manuscript published: October 13, 2020 (version 1)
  4. Version of Record published: October 28, 2020 (version 2)

Copyright

© 2020, Cheng 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

  • 2,157
    Page views
  • 349
    Downloads
  • 32
    Citations

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

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. Ryan R Cheng
  2. Vinicius Contessoto
  3. Erez Lieberman-Aiden
  4. Peter G Wolynes
  5. Michele Di Pierro
  6. Jose N Onuchic
(2020)
Exploring chromosomal structural heterogeneity across multiple cell lines
eLife 9:e60312.
https://doi.org/10.7554/eLife.60312

Share this article

https://doi.org/10.7554/eLife.60312

Further reading

    1. Chromosomes and Gene Expression
    Allison Coté, Aoife O'Farrell ... Arjun Raj
    Research Article

    Splicing is the stepwise molecular process by which introns are removed from pre-mRNA and exons are joined together to form mature mRNA sequences. The ordering and spatial distribution of these steps remain controversial, with opposing models suggesting splicing occurs either during or after transcription. We used single-molecule RNA FISH, expansion microscopy, and live-cell imaging to reveal the spatiotemporal distribution of nascent transcripts in mammalian cells. At super-resolution levels, we found that pre-mRNA formed clouds around the transcription site. These clouds indicate the existence of a transcription-site-proximal zone through which RNA move more slowly than in the nucleoplasm. Full-length pre-mRNA undergo continuous splicing as they move through this zone following transcription, suggesting a model in which splicing can occur post-transcriptionally but still within the proximity of the transcription site, thus seeming co-transcriptional by most assays. These results may unify conflicting reports of co-transcriptional versus post-transcriptional splicing.

    1. Chromosomes and Gene Expression
    Fujun Zhou, Julie M Bocetti ... Jon R Lorsch
    Research Article

    We have developed a deep sequencing-based approach, Rec-Seq, that allows simultaneous monitoring of ribosomal 48S preinitiation complex (PIC) formation on every mRNA in the translatome in an in vitro reconstituted system. Rec-Seq isolates key early steps in translation initiation in the absence of all other cellular components and processes. Using this approach, we show that the DEAD-box ATPase Ded1 promotes 48S PIC formation on the start codons of >1000 native mRNAs, most of which have long, structured 5′-untranslated regions (5′UTRs). Remarkably, initiation measured in Rec-Seq was enhanced by Ded1 for most mRNAs previously shown to be highly Ded1-dependent by ribosome profiling of ded1 mutants in vivo, demonstrating that the core translation functions of the factor are recapitulated in the purified system. Our data do not support a model in which Ded1acts by reducing initiation at alternative start codons in 5′UTRs and instead indicate it functions by directly promoting mRNA recruitment to the 43S PIC and scanning to locate the main start codon. We also provide evidence that eIF4A, another essential DEAD-box initiation factor, is required for efficient PIC assembly on almost all mRNAs, regardless of their structural complexity, in contrast to the preferential stimulation by Ded1 of initiation on mRNAs with long, structured 5′UTRs.