title: Patterns of regulatory activity across diverse human cell types predict tissue identity, transcription factor binding, and long-range interactions.
abstract: Regulatory elements recruit transcription factors that modulate gene expression distinctly across cell types, but the relationships among these remains elusive. To address this, we analyzed matched DNase-seq and gene expression data for 112 human samples representing 72 cell types. We first defined more than 1800 clusters of DNase I hypersensitive sites (DHSs) with similar tissue specificity of DNase-seq signal patterns. We then used these to uncover distinct associations between DHSs and promoters, CpG islands, conserved elements, and transcription factor motif enrichment. Motif analysis within clusters identified known and novel motifs in cell-type-specific and ubiquitous regulatory elements and supports a role for AP-1 regulating open chromatin. We developed a classifier that accurately predicts cell-type lineage based on only 43 DHSs and evaluated the tissue of origin for cancer cell types. A similar classifier identified three sex-specific loci on the X chromosome, including the XIST lincRNA locus. By correlating DNase I signal and gene expression, we predicted regulated genes for more than 500K DHSs. Finally, we introduce a web resource to enable researchers to use these results to explore these regulatory patterns and better understand how expression is modulated within and across human cell types.
authors.affiliation: Program in Computational Biology and Bioinformatics, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Sheffield
authors.forename: Robert E
authors.initials: RE
authors.lastname: Thurman
authors.forename: Lingyun
authors.initials: L
authors.lastname: Song
authors.forename: Alexias
authors.initials: A
authors.lastname: Safi
authors.forename: John A
authors.initials: JA
authors.lastname: Stamatoyannopoulos
authors.forename: Boris
authors.initials: B
authors.lastname: Lenhard
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Crawford
authors.forename: Terrence S
authors.initials: TS
authors.lastname: Furey
mesh_terms: D001665:Binding Sites / Q000235:genetics; D002477:Cells / Q000145:classification / Q000166:cytology / Q000378:metabolism*; D002843:Chromatin / Q000235:genetics; D002874:Chromosome Mapping; D004268:DNA-Binding Proteins / Q000235:genetics*; D003850:Deoxyribonuclease I / Q000235:genetics*; D005786:Gene Expression Regulation; D015894:Genome, Human; D006801:Humans; D006967:Hypersensitivity; D009928:Organ Specificity; D011485:Protein Binding / Q000235:genetics; D050436:Regulatory Elements, Transcriptional / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000235:genetics
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D018808:Transcription Factor AP-1; D003850:Deoxyribonuclease I