Cited by 219Genomics and Chromatin DynamicsGenomics and Phylogenetic StudiesChromatin Remodeling and Cancer

Refined DNase-seq protocol and data analysis reveals intrinsic bias in transcription factor footprint identification

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He, Housheng Hansen, Meyer, Clifford A, Hu, Sheng'en Shawn, Chen, Mei-Wei, Zang, Chongzhi, Liu, Yin, Rao, Prakash K, Fei, Teng +4 more·2014·Nature Methods

Abstract

Sequencing of DNase I hypersensitive sites (DNase-seq) is a powerful technique for identifying cis-regulatory elements across the genome. We studied the key experimental parameters to optimize performance of DNase-seq. Sequencing short fragments of 50-100 base pairs (bp) that accumulate in long internucleosome linker regions was more efficient for identifying transcription factor binding sites compared to sequencing longer fragments. We also assessed the potential of DNase-seq to predict transcription factor occupancy via generation of nucleotide-resolution transcription factor footprints. In modeling the sequence-specific DNase I cutting bias, we found a strong effect that varied over more than two orders of magnitude. This indicates that the nucleotide-resolution cleavage patterns at many transcription factor binding sites are derived from intrinsic DNase I cleavage bias rather than from specific protein-DNA interactions. In contrast, quantitative comparison of DNase I hypersensitivity between states can predict transcription factor occupancy associated with particular biological perturbations.

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  • Adding a methyl group to cytosine can affect local DNA shape, as shown by altered DNase I digestion rate and patterns.

    “Adding a methyl group to the cytosine could affect the local DNA shape, as evidenced by the altered DNase I digestion rate and patterns70,71.”

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Authors
He, H. H., Meyer, C. A., Hu, S. S., Chen, M.-W., Zang, C., Liu, Y., Rao, P. K., Fei, T., Xu, H., Long, H., Liu, X. S., & Brown, M.
Affiliations
  • University Health Network (CA)
  • Harvard University (US)
  • Dana-Farber Cancer Institute (US)
  • Tongji University (CN)
Corresponding author
  • Long, Henry
  • Liu, X Shirley
  • Brown, Myles
Venue
Nature Methods
Published
2013-12-08
Volume
11
Issue
1
Pages
73-78
ISSN
  • 1548-7091 (ISSN-L)
  • 1548-7105
OpenAlex
W2009853003
Cited by
218
References
22
Citations by year
2026: 8 · 2025: 4 · 2024: 14 · 2023: 6 · 2022: 10 · 2021: 17 · 2020: 13 · 2019: 30 · 2018: 28 · 2017: 24 · 2016: 26 · 2015: 18 · 2014: 18 · 2013: 1
FWCI
9.41
Type
journal article
Language
en
Open access
Locations
  • Nature Methods (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
Funders
  • National Human Genome Research Institute (U41HG007000)
  • National Cancer Institute (K99CA172948, P50CA090381)
  • National Institute of General Medical Sciences (R01GM099409)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK074967)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
DNase-seq, DNase I hypersensitive sites, transcription factor footprints, cis-regulatory elements, transcription factor binding sites, DNase I hypersensitivity, transcription factor occupancy, protocol optimization
MeSH terms
Binding Sites, Chromatin, Deoxyribonuclease I, Female, Gene Expression Regulation, Humans, Male, Nucleosomes, Nucleotides, Receptors, Androgen, Transcription Factors, Tumor Suppressor Protein p53, Sequence Analysis, DNA, K562 Cells, Amino Acid Motifs, Cell Line, Tumor, Gene Regulatory Networks, MCF-7 Cells

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