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

  • 2,033
    Page views
  • 328
    Downloads
  • 29
    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

Further reading

    1. Cell Biology
    2. Chromosomes and Gene Expression
    Maikel Castellano-Pozo, Georgios Sioutas ... Enrique Martinez-Perez
    Short Report Updated

    The cohesin complex plays essential roles in chromosome segregation, 3D genome organisation, and DNA damage repair through its ability to modify DNA topology. In higher eukaryotes, meiotic chromosome function, and therefore fertility, requires cohesin complexes containing meiosis-specific kleisin subunits: REC8 and RAD21L in mammals and REC-8 and COH-3/4 in Caenorhabditis elegans. How these complexes perform the multiple functions of cohesin during meiosis and whether this involves different modes of DNA binding or dynamic association with chromosomes is poorly understood. Combining time-resolved methods of protein removal with live imaging and exploiting the temporospatial organisation of the C. elegans germline, we show that REC-8 complexes provide sister chromatid cohesion (SCC) and DNA repair, while COH-3/4 complexes control higher-order chromosome structure. High-abundance COH-3/4 complexes associate dynamically with individual chromatids in a manner dependent on cohesin loading (SCC-2) and removal (WAPL-1) factors. In contrast, low-abundance REC-8 complexes associate stably with chromosomes, tethering sister chromatids from S-phase until the meiotic divisions. Our results reveal that kleisin identity determines the function of meiotic cohesin by controlling the mode and regulation of cohesin–DNA association, and are consistent with a model in which SCC and DNA looping are performed by variant cohesin complexes that coexist on chromosomes.

    1. Chromosomes and Gene Expression
    2. Developmental Biology
    Airat Ibragimov, Xin Yang Bing ... Paul Schedl
    Research Article Updated

    Though long non-coding RNAs (lncRNAs) represent a substantial fraction of the Pol II transcripts in multicellular animals, only a few have known functions. Here we report that the blocking activity of the Bithorax complex (BX-C) Fub-1 boundary is segmentally regulated by its own lncRNA. The Fub-1 boundary is located between the Ultrabithorax (Ubx) gene and the bxd/pbx regulatory domain, which is responsible for regulating Ubx expression in parasegment PS6/segment A1. Fub-1 consists of two hypersensitive sites, HS1 and HS2. HS1 is an insulator while HS2 functions primarily as an lncRNA promoter. To activate Ubx expression in PS6/A1, enhancers in the bxd/pbx domain must be able to bypass Fub-1 blocking activity. We show that the expression of the Fub-1 lncRNAs in PS6/A1 from the HS2 promoter inactivates Fub-1 insulating activity. Inactivation is due to read-through as the HS2 promoter must be directed toward HS1 to disrupt blocking.