1. Computational and Systems Biology
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A network of epigenetic modifiers and DNA repair genes controls tissue-specific copy number alteration preference

  1. Dina Cramer
  2. Luis Serrano  Is a corresponding author
  3. Martin H Schaefer  Is a corresponding author
  1. The Barcelona Institute of Science and Technology, Spain
Research Article
  • Cited 6
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Cite this article as: eLife 2016;5:e16519 doi: 10.7554/eLife.16519

Abstract

Copy number alterations (CNAs) in cancer patients show a large variability in their number, length and position. CNA number and length are linked to patient survival suggesting clinical relevance. However, the sources of this variability are not known. We have identified genes that tend to be mutated in samples having few or many CNAs, which we term CONIM genes (COpy Number Instability Modulators). CONIM proteins cluster into a densely connected subnetwork of physical interactions and many of them are epigenetic modifiers. Therefore, we investigate how the epigenome of the tissue-of-origin influences the position of CNA breakpoints and the properties of the resulting CNAs. We find that the presence of heterochromatin in the tissue-of-origin contributes to the recurrence and length of CNAs in the respective cancer type.

Data availability

The following previously published data sets were used
    1. Kundaje
    2. A. et al.
    (2015) Histone ChIP-seq peaks
    Publicly available at NIH Roadmap Epigenomics Mapping Consortium.

Article and author information

Author details

  1. Dina Cramer

    EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  2. Luis Serrano

    EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain
    For correspondence
    luis.serrano@crg.eu
    Competing interests
    The authors declare that no competing interests exist.
  3. Martin H Schaefer

    EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain
    For correspondence
    martin.schaefer@crg.eu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7503-6364

Funding

Deutsche Forschungsgemeinschaft (SCHA 1933/1-1)

  • Martin H Schaefer

European Commission (HEALTH-F4-2011-278568)

  • Luis Serrano

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

Reviewing Editor

  1. Jason Ernst, University of California, Los Angeles, United States

Publication history

  1. Received: March 30, 2016
  2. Accepted: November 2, 2016
  3. Accepted Manuscript published: November 10, 2016 (version 1)
  4. Version of Record published: November 24, 2016 (version 2)

Copyright

© 2016, Cramer 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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Further reading

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    Background:

    Predicting neurological recovery after spinal cord injury (SCI) is challenging. Using topological data analysis, we have previously shown that mean arterial pressure (MAP) during SCI surgery predicts long-term functional recovery in rodent models, motivating the present multicenter study in patients.

    Methods:

    Intra-operative monitoring records and neurological outcome data were extracted (n = 118 patients). We built a similarity network of patients from a low-dimensional space embedded using a non-linear algorithm, Isomap, and ensured topological extraction using persistent homology metrics. Confirmatory analysis was conducted through regression methods.

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    Network analysis suggested that time outside of an optimum MAP range (hypotension or hypertension) during surgery was associated with lower likelihood of neurological recovery at hospital discharge. Logistic and LASSO (least absolute shrinkage and selection operator) regression confirmed these findings, revealing an optimal MAP range of 76–[104-117] mmHg associated with neurological recovery.

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    We show that deviation from this optimal MAP range during SCI surgery predicts lower probability of neurological recovery and suggest new targets for therapeutic intervention.

    Funding:

    NIH/NINDS: R01NS088475 (ARF); R01NS122888 (ARF); UH3NS106899 (ARF); Department of Veterans Affairs: 1I01RX002245 (ARF), I01RX002787 (ARF); Wings for Life Foundation (ATE, ARF); Craig H. Neilsen Foundation (ARF); and DOD: SC150198 (MSB); SC190233 (MSB); DOE: DE-AC02-05CH11231 (DM).

    1. Computational and Systems Biology
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    Ligand-gated ion channels conduct currents in response to chemical stimuli, mediating electrochemical signaling in neurons and other excitable cells. For many channels, the details of gating remain unclear, partly due to limited structural data and simulation timescales. Here, we used enhanced sampling to simulate the pH-gated channel GLIC, and construct Markov state models (MSMs) of gating. Consistent with new functional recordings, we report in oocytes, our analysis revealed differential effects of protonation and mutation on free-energy wells. Clustering of closed- versus open-like states enabled estimation of open probabilities and transition rates, while higher-order clustering affirmed conformational trends in gating. Furthermore, our models uncovered state- and protonation-dependent symmetrization. This demonstrates the applicability of MSMs to map energetic and conformational transitions between ion-channel functional states, and how they reproduce shifts upon activation or mutation, with implications for modeling neuronal function and developing state-selective drugs.