title: Refined DNase-seq protocol and data analysis reveals intrinsic bias in transcription factor footprint identification.
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.
authors: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts 02115, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.|Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Ontario Cancer Institute, Princess Margaret Cancer Center/University Health Network, Toronto, Ontario, M5G1L7, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G2M9, Canada.
authors: Housheng Hansen
authors: HH
authors: He
authors: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts 02115, USA.|Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors: Clifford A
authors: CA
authors: Meyer
authors: Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai, 20092, China.
authors: Sheng'en Shawn
authors: SS
authors: Hu
authors: Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors: Mei-Wei
authors: MW
authors: Chen
authors: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts 02115, USA.|Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors: Chongzhi
authors: C
authors: Zang
authors: Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai, 20092, China.
authors: Yin
authors: Y
authors: Liu
authors: Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors: Prakash K
authors: PK
authors: Rao
authors: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts 02115, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.|Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors: Teng
authors: T
authors: Fei
authors: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts 02115, USA.|Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors: Han
authors: H
authors: Xu
authors: Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors: Henry
authors: H
authors: Long
authors: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts 02115, USA.|Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors: X Shirley
authors: XS
authors: Liu
authors: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.|Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors: Myles
authors: M
authors: Brown
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry; D003850:Deoxyribonuclease I / Q000737:chemistry*; D005260:Female; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D020014:K562 Cells; D061986:MCF-7 Cells; D008297:Male; D009707:Nucleosomes / Q000737:chemistry; D009711:Nucleotides / Q000737:chemistry; D011944:Receptors, Androgen / Q000737:chemistry; D017422:Sequence Analysis, DNA / Q000379:methods*; D014157:Transcription Factors / Q000737:chemistry*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry
chemical_list: D002843:Chromatin; D009707:Nucleosomes; D009711:Nucleotides; D011944:Receptors, Androgen; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D003850:Deoxyribonuclease I