Document Type

Article

Publication Date

1-25-2019

Keywords

JGM

JAX Source

Nucleic Acids 2019 Jan 25; 47(2):e11

Volume

47

Issue

2

First Page

11

Last Page

11

ISSN

1362-4962

PMID

30428075

DOI

https://doi.org/10.1093/nar/gky1117

Grant

GM124922, The Jackson Laboratory Startup Funds

Abstract

Transcription factor (TF) footprinting uncovers putative protein-DNA binding via combined analyses of chromatin accessibility patterns and their underlying TF sequence motifs. TF footprints are frequently used to identify TFs that regulate activities of cell/condition-specific genomic regions (target loci) in comparison to control regions (background loci) using standard enrichment tests. However, there is a strong association between the chromatin accessibility level and the GC content of a locus and the number and types of TF footprints that can be detected at this site. Traditional enrichment tests (e.g. hypergeometric) do not account for this bias and inflate false positive associations. Therefore, we developed a novel post-processing method, Bias-free Footprint Enrichment Test (BiFET), that corrects for the biases arising from the differences in chromatin accessibility levels and GC contents between target and background loci in footprint enrichment analyses. We applied BiFET on TF footprint calls obtained from EndoC-βH1 ATAC-seq samples using three different algorithms (CENTIPEDE, HINT-BC and PIQ) and showed BiFET's ability to increase power and reduce false positive rate when compared to hypergeometric test. Furthermore, we used BiFET to study TF footprints from human PBMC and pancreatic islet ATAC-seq samples to show its utility to identify putative TFs associated with cell-type-specific loci.

Comments

This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License

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