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Title: Limb-Enhancer Genie: An accessible resource of accurate enhancer predictions in the developing limb

Abstract

Epigenomic mapping of enhancer-associated chromatin modifications facilitates the genome-wide discovery of tissue-specific enhancers in vivo. However, reliance on single chromatin marks leads to high rates of false-positive predictions. More sophisticated, integrative methods have been described, but commonly suffer from limited accessibility to the resulting predictions and reduced biological interpretability. Here we present the Limb-Enhancer Genie (LEG), a collection of highly accurate, genome-wide predictions of enhancers in the developing limb, available through a user-friendly online interface. We predict limb enhancers using a combination of > 50 published limb-specific datasets and clusters of evolutionarily conserved transcription factor binding sites, taking advantage of the patterns observed at previously in vivo validated elements. By combining different statistical models, our approach outperforms current state-of-the-art methods and provides interpretable measures of feature importance. Our results indicate that including a previously unappreciated score that quantifies tissue-specific nuclease accessibility significantly improves prediction performance. We demonstrate the utility of our approach through in vivo validation of newly predicted elements. Moreover, we describe general features that can guide the type of datasets to include when predicting tissue-specific enhancers genome-wide, while providing an accessible resource to the general biological community and facilitating the functional interpretation of genetic studies of limb malformations.

Authors:
 [1]; ORCiD logo [2]; ORCiD logo [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2]; ORCiD logo [3];  [2];  [4];  [1];  [5]
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States)
  2. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  3. ETH Zurich (Switzerland). Dept. of Biosystems Science and Engineering
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States); Univ. of California, Merced, CA (United States). School of Natural Sciences
  5. Ottawa Univ., ON (Canada)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1408453
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
PLoS Computational Biology (Online)
Additional Journal Information:
Journal Name: PLoS Computational Biology (Online); Journal Volume: 13; Journal Issue: 8; Journal ID: ISSN 1553-7358
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Monti, Remo, Barozzi, Iros, Osterwalder, Marco, Lee, Elizabeth, Kato, Momoe, Garvin, Tyler H., Plajzer-Frick, Ingrid, Pickle, Catherine S., Akiyama, Jennifer A., Afzal, Veena, Beerenwinkel, Niko, Dickel, Diane E., Visel, Axel, Pennacchio, Len A., and Ioshikhes, Ilya. Limb-Enhancer Genie: An accessible resource of accurate enhancer predictions in the developing limb. United States: N. p., 2017. Web. doi:10.1371/journal.pcbi.1005720.
Monti, Remo, Barozzi, Iros, Osterwalder, Marco, Lee, Elizabeth, Kato, Momoe, Garvin, Tyler H., Plajzer-Frick, Ingrid, Pickle, Catherine S., Akiyama, Jennifer A., Afzal, Veena, Beerenwinkel, Niko, Dickel, Diane E., Visel, Axel, Pennacchio, Len A., & Ioshikhes, Ilya. Limb-Enhancer Genie: An accessible resource of accurate enhancer predictions in the developing limb. United States. doi:10.1371/journal.pcbi.1005720.
Monti, Remo, Barozzi, Iros, Osterwalder, Marco, Lee, Elizabeth, Kato, Momoe, Garvin, Tyler H., Plajzer-Frick, Ingrid, Pickle, Catherine S., Akiyama, Jennifer A., Afzal, Veena, Beerenwinkel, Niko, Dickel, Diane E., Visel, Axel, Pennacchio, Len A., and Ioshikhes, Ilya. Mon . "Limb-Enhancer Genie: An accessible resource of accurate enhancer predictions in the developing limb". United States. doi:10.1371/journal.pcbi.1005720. https://www.osti.gov/servlets/purl/1408453.
@article{osti_1408453,
title = {Limb-Enhancer Genie: An accessible resource of accurate enhancer predictions in the developing limb},
author = {Monti, Remo and Barozzi, Iros and Osterwalder, Marco and Lee, Elizabeth and Kato, Momoe and Garvin, Tyler H. and Plajzer-Frick, Ingrid and Pickle, Catherine S. and Akiyama, Jennifer A. and Afzal, Veena and Beerenwinkel, Niko and Dickel, Diane E. and Visel, Axel and Pennacchio, Len A. and Ioshikhes, Ilya},
abstractNote = {Epigenomic mapping of enhancer-associated chromatin modifications facilitates the genome-wide discovery of tissue-specific enhancers in vivo. However, reliance on single chromatin marks leads to high rates of false-positive predictions. More sophisticated, integrative methods have been described, but commonly suffer from limited accessibility to the resulting predictions and reduced biological interpretability. Here we present the Limb-Enhancer Genie (LEG), a collection of highly accurate, genome-wide predictions of enhancers in the developing limb, available through a user-friendly online interface. We predict limb enhancers using a combination of > 50 published limb-specific datasets and clusters of evolutionarily conserved transcription factor binding sites, taking advantage of the patterns observed at previously in vivo validated elements. By combining different statistical models, our approach outperforms current state-of-the-art methods and provides interpretable measures of feature importance. Our results indicate that including a previously unappreciated score that quantifies tissue-specific nuclease accessibility significantly improves prediction performance. We demonstrate the utility of our approach through in vivo validation of newly predicted elements. Moreover, we describe general features that can guide the type of datasets to include when predicting tissue-specific enhancers genome-wide, while providing an accessible resource to the general biological community and facilitating the functional interpretation of genetic studies of limb malformations.},
doi = {10.1371/journal.pcbi.1005720},
journal = {PLoS Computational Biology (Online)},
number = 8,
volume = 13,
place = {United States},
year = {Mon Aug 21 00:00:00 EDT 2017},
month = {Mon Aug 21 00:00:00 EDT 2017}
}

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Works referenced in this record:

Random Forests
journal, January 2001