Abstract
The study of gene regulation is dominated by a focus on the control of gene activation or increase in the level of expression. Just as critical is the process of gene repression or silencing. Chromatin signatures have identified enhancers, however, genome-wide identification of silencers by computational or experimental approaches are lacking. Here, we first define uncharacterized cis-regulatory elements likely containing silencers and find that 41.5% of ~7500 tested elements show silencer activity using massively parallel reporter assay (MPRA). We trained a support vector machine classifier based on MPRA data to predict candidate silencers in over 100 human and mouse cell or tissue types. The predicted candidate silencers exhibit characteristics expected of silencers. Leveraging promoter-capture HiC data, we find that over 50% of silencers are interacting with gene promoters having very low to no expression. Our results suggest a general strategy for genome-wide identification and characterization of silencer elements.
Highlights
The study of gene regulation is dominated by a focus on the control of gene activation or increase in the level of expression
In order to identify silencer elements, first we devised a simple subtractive analysis approach based on DNase hypersensitive sites (DHS) and other known cis-regulatory elements (CREs) to find the DHS elements lacking known chromatin marks belonging to promoters, enhancers, and CTCF-bound insulators, and we term these elements as uncharacterized CREs
In order to find genome-wide candidate silencer elements, first we devised an efficient simple subtractive analysis (SSA) approach to determine DHS elements lacking known chromatin marks belonging to promoters and enhancers, or CTCF binding for insulators, and we term these elements as uncharacterized CREs (Fig. 1a)
Summary
The study of gene regulation is dominated by a focus on the control of gene activation or increase in the level of expression. Silencers along with enhancers and insulators create a complex array of distal cis-regulatory elements (CREs) These elements, and the factors that bind to them, are important for the nuanced output of RNA levels across cell types. While the presence of repressor sequences within CREs such as promoters has recently become more evident by tiling millions of oligos across these regions and testing by massively parallel reporter assays (MPRA)[26], distinct annotations for distal silencer elements in the human and mouse genomes are still missing from our cis-regulatory lexicon. Using MPRA data, we trained a support vector machine (SVM) classifier to predict potential candidate silencer elements from untested uncharacterized CREs in 82 human and 22 mouse cell or tissue types. These catalogs, which will require more intensive study and validation from the field, should aid our understanding of gene expression through negative regulation of expression
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