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An atlas of silencer elements for the human and mouse genomes

Naresh Doni Jayavelu, Ajay Jajodia, Arpit Mishra, R. David Hawkins
doi: https://doi.org/10.1101/252304
Naresh Doni Jayavelu
1Division of Medical Genetics, Department of Medicine, Department of Genome Sciences, Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA USA
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Ajay Jajodia
1Division of Medical Genetics, Department of Medicine, Department of Genome Sciences, Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA USA
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Arpit Mishra
1Division of Medical Genetics, Department of Medicine, Department of Genome Sciences, Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA USA
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R. David Hawkins
1Division of Medical Genetics, Department of Medicine, Department of Genome Sciences, Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA USA
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  • For correspondence: rdhawk@uw.edu
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ABSTRACT

The study of gene regulation is dominated by a focus on the control of gene activation or controlling an increase in the level of expression. Just as critical is the process of gene repression or silencing. Chromatin signatures have allowed for the global mapping of enhancer cis-regulatory elements, however, the identification of silencer elements by computational or experimental approaches in a genome-wide manner are lacking. We present a simple but powerful computational approach to identify putative silencers genome-wide. We used a series of consortia data to predict silencers in over 100 human and mouse cell or tissue types. We performed several analyses to determine if these elements exhibited characteristics expected of a silencers. Motif enrichment analyses on putative silencers determined that motifs belonging to known transcriptional repressors are enriched, as well as overlapping known transcription repressor binding sites. Leveraging promoter capture HiC data from several human and mouse cell types, we found that over 50% of putative silencer elements are interacting with gene promoters having very low to no expression. Next, to validate our silencer predictions, we quantified silencer activity using massively parallel reporter assays (MPRAs) on 7500 selected elements in K562 cells. We trained a support vector machine model classifier on MPRA data and used it to refine potential silencers in other cell types. We also show that similar to enhancer elements, silencer elements are enriched in disease-associated variants. Our results suggest a general strategy for genome-wide identification and characterization of silencer elements.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted January 23, 2018.
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An atlas of silencer elements for the human and mouse genomes
Naresh Doni Jayavelu, Ajay Jajodia, Arpit Mishra, R. David Hawkins
bioRxiv 252304; doi: https://doi.org/10.1101/252304
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An atlas of silencer elements for the human and mouse genomes
Naresh Doni Jayavelu, Ajay Jajodia, Arpit Mishra, R. David Hawkins
bioRxiv 252304; doi: https://doi.org/10.1101/252304

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