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Genome-wide discovery of active regulatory elements and transcription factor footprints in Caenorhabditis elegans using DNase-seq

Ho, Margaret C. W. and Quintero-Cadena, Porfirio and Sternberg, Paul W. (2017) Genome-wide discovery of active regulatory elements and transcription factor footprints in Caenorhabditis elegans using DNase-seq. Genome Research, 27 (12). pp. 2108-2119. ISSN 1088-9051. PMCID PMC5741056. https://resolver.caltech.edu/CaltechAUTHORS:20171030-102102638

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Abstract

Deep sequencing of size-selected DNase I–treated chromatin (DNase-seq) allows high-resolution measurement of chromatin accessibility to DNase I cleavage, permitting identification of de novo active cis-regulatory modules (CRMs) and individual transcription factor (TF) binding sites. We adapted DNase-seq to nuclei isolated from C. elegans embryos and L1 arrest larvae to generate high-resolution maps of TF binding. Over half of embryonic DNase I hypersensitive sites (DHSs) were annotated as noncoding, with 24% in intergenic, 12% in promoters, and 28% in introns, with similar statistics observed in L1 arrest larvae. Noncoding DHSs are highly conserved and enriched in marks of enhancer activity and transcription. We validated noncoding DHSs against known enhancers from myo-2, myo-3, hlh-1, elt-2, and lin-26/lir-1 and recapitulated 15 of 17 known enhancers. We then mined DNase-seq data to identify putative active CRMs and TF footprints. Using DNase-seq data improved predictions of tissue-specific expression compared with motifs alone. In a pilot functional test, 10 of 15 DHSs from pha-4, icl-1, and ceh-13 drove reporter gene expression in transgenic C. elegans. Overall, we provide experimental annotation of 26,644 putative CRMs in the embryo containing 55,890 TF footprints, as well as 15,841 putative CRMs in the L1 arrest larvae containing 32,685 TF footprints.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/gr.223735.117DOIArticle
http://genome.cshlp.org/content/27/12/2108PublisherArticle
http://genome.cshlp.org/content/27/12/2108/suppl/DC1PublisherSupplemental Material
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741056/PubMed CentralArticle
ORCID:
AuthorORCID
Quintero-Cadena, Porfirio0000-0003-0067-5844
Sternberg, Paul W.0000-0002-7699-0173
Additional Information:© 2017 Ho et al.; Published by Cold Spring Harbor Laboratory Press This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/. Received April 6, 2017; Accepted October 18, 2017; Published in Advance October 26, 2017. Data access: The DNase-seq data from this study have been submitted to the NCBI Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo/) under accession number GSE97425. Additional analysis files, including DNase I signal data, all DHSs and nearest genes, putative TF footprints, novel motifs, motif-associated genes, and GO analysis, are available from WormBase (detailed list of files in Supplemental Table S3). We thank WormBase, especially Xiaodong Wang and James Done. This research was supported by NIH (National Institute of General Medical Sciences) grant GM084389 to P.W.S. and the Howard Hughes Medical Institute (047101), with which P.W.S. is an investigator. M.C.W.H. was supported by a National Science Foundation GRFP predoctoral fellowship. We would like to thank Ali Mortazavi, Igor Antoshechkin, John DeModena, Steven Kuntz, Erich Schwarz, Jim McGhee, and Erin Osborne Nishimura for assistance and advice on experimental design, sequence library construction, and analysis and interpretation of data. We thank David Angeles for help performing anatomy enrichment analysis. We thank Mark Wu, Mihoko Kato, and Hillel Schwartz for helpful suggestions on the manuscript.
Group:WormBase
Funders:
Funding AgencyGrant Number
NIHGM084389
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
NSF Graduate Research FellowshipUNSPECIFIED
Subject Keywords:cis-regulatory modules, gene regulation, enhancers, nematode development, transcription, DNase, hypersensitivity
Issue or Number:12
PubMed Central ID:PMC5741056
Record Number:CaltechAUTHORS:20171030-102102638
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20171030-102102638
Official Citation:Genome-wide discovery of active regulatory elements and transcription factor footprints in Caenorhabditis elegans using DNase-seq Margaret C.W. Ho, Porfirio Quintero-Cadena, and Paul W. Sternberg Genome Res. December 2017 27: 2108-2119; Published in Advance October 26, 2017, doi:10.1101/gr.223735.117
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:82769
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:30 Oct 2017 17:34
Last Modified:03 Oct 2019 18:58

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