title: Discovering hotspots in functional genomic data superposed on 3D chromatin configuration reconstructions.
abstract: The spatial organization of the genome influences cellular function, notably gene regulation. Recent studies have assessed the three-dimensional (3D) co-localization of functional annotations (e.g. centromeres, long terminal repeats) using 3D genome reconstructions from Hi-C (genome-wide chromosome conformation capture) data; however, corresponding assessments for continuous functional genomic data (e.g. chromatin immunoprecipitation-sequencing (ChIP-seq) peak height) are lacking. Here, we demonstrate that applying bump hunting via the patient rule induction method (PRIM) to ChIP-seq data superposed on a Saccharomyces cerevisiae 3D genome reconstruction can discover 'functional 3D hotspots', regions in 3-space for which the mean ChIP-seq peak height is significantly elevated. For the transcription factor Swi6, the top hotspot by P-value contains MSB2 and ERG11 - known Swi6 target genes on different chromosomes. We verify this finding in a number of ways. First, this top hotspot is relatively stable under PRIM across parameter settings. Second, this hotspot is among the top hotspots by mean outcome identified by an alternative algorithm, k-Nearest Neighbor (k-NN) regression. Third, the distance between MSB2 and ERG11 is smaller than expected (by resampling) in two other 3D reconstructions generated via different normalization and reconstruction algorithms. This analytic approach can discover functional 3D hotspots and potentially reveal novel regulatory interactions.
authors: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158, USA.
authors: Daniel
authors: D
authors: Capurso
authors: Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94158, USA.
authors: Henrik
authors: H
authors: Bengtsson
authors: Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94158, USA Mark.Segal@ucsf.edu.
authors: Mark R
authors: MR
authors: Segal
mesh_terms: D000465:Algorithms; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure*; D047369:Chromatin Immunoprecipitation; D002874:Chromosome Mapping; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D016681:Genome, Fungal; D059014:High-Throughput Nucleotide Sequencing; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D002843:Chromatin; D047908:Intracellular Signaling Peptides and Proteins; C076360:MSB2 protein, S cerevisiae; C075111:SWI6 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D003577:Cytochrome P-450 Enzyme System; C526348:Erg11 protein, S cerevisiae