1. Effect of natural genetic variation on enhancer selection and function.
- Author
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Heinz S, Romanoski CE, Benner C, Allison KA, Kaikkonen MU, Orozco LD, and Glass CK
- Subjects
- Amino Acid Motifs genetics, Animals, Base Sequence, Cell Lineage genetics, DNA-Binding Proteins metabolism, Histones chemistry, Histones metabolism, Macrophages metabolism, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Models, Biological, Mutation genetics, NF-kappa B metabolism, Protein Binding, Reproducibility of Results, Transcription Factor RelA metabolism, Enhancer Elements, Genetic genetics, Gene Expression Regulation genetics, Genetic Variation genetics, Selection, Genetic genetics, Transcription Factors metabolism
- 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.
- Published
- 2013
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