title: Effect of natural genetic variation on enhancer selection and function.
abstract: The mechanisms by which genetic variation affects transcription regulation and phenotypes at the nucleotide level are incompletely understood. Here we use natural genetic variation as an in vivo mutagenesis screen to assess the genome-wide effects of sequence variation on lineage-determining and signal-specific transcription factor binding, epigenomics and transcriptional outcomes in primary macrophages from different mouse strains. We find substantial genetic evidence to support the concept that lineage-determining transcription factors define epigenetic and transcriptomic states by selecting enhancer-like regions in the genome in a collaborative fashion and facilitating binding of signal-dependent factors. This hierarchical model of transcription factor function suggests that limited sets of genomic data for lineage-determining transcription factors and informative histone modifications can be used for the prioritization of disease-associated regulatory variants.
authors.affiliation: 1] Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, Mail Code 0651, La Jolla, California 92093, USA [2].
authors.forename: S
authors.initials: S
authors.lastname: Heinz
authors.forename: C E
authors.initials: CE
authors.lastname: Romanoski
authors.forename: C
authors.initials: C
authors.lastname: Benner
authors.forename: K A
authors.initials: KA
authors.lastname: Allison
authors.forename: M U
authors.initials: MU
authors.lastname: Kaikkonen
authors.forename: L D
authors.initials: LD
authors.lastname: Orozco
authors.forename: C K
authors.initials: CK
authors.lastname: Glass
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D019070:Cell Lineage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D015203:Reproducibility of Results; D012641:Selection, Genetic / Q000235:genetics*; D051996:Transcription Factor RelA / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D016328:NF-kappa B; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014157:Transcription Factors