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Epigenetics Chromatin. 2019 Jun 4;12(1):30. doi: 10.1186/s13072-019-0277-6.

XL-DNase-seq: improved footprinting of dynamic transcription factors.

Author information

1
Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA.
2
Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, 41 Library Drive, Bethesda, MD, 20892, USA.
3
Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA. sungm@mail.nih.gov.

Abstract

BACKGROUND:

As the cost of high-throughput sequencing technologies decreases, genome-wide chromatin accessibility profiling methods such as the assay of transposase-accessible chromatin using sequencing (ATAC-seq) are employed widely, with data accumulating at an unprecedented rate. However, accurate inference of protein occupancy requires higher-resolution footprinting analysis where major hurdles exist, including the sequence bias of nucleases and the short-lived chromatin binding of many transcription factors (TFs) with consequent lack of footprints.

RESULTS:

Here we introduce an assay termed cross-link (XL)-DNase-seq, designed to capture chromatin interactions of dynamic TFs. Mild cross-linking improved the detection of DNase-based footprints of dynamic TFs but interfered with ATAC-based footprinting of the same TFs.

CONCLUSIONS:

XL-DNase-seq may help extract novel gene regulatory circuits involving previously undetectable TFs. The DNase-seq and ATAC-seq data generated in our systematic comparison of various cross-linking conditions also represent an unprecedented-scale resource derived from activated mouse macrophage-like cells which share many features of inflammatory macrophages.

KEYWORDS:

ATAC-seq; Bioinformatics; Chromatin accessibility; Computational genomics; DNase-seq; Epigenomics; Genomic footprinting; High-throughput sequencing; Transcription factor binding motifs; Transcription factor footprinting

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