Effect of natural genetic variation on enhancer selection and function

• Published in: Nature (London) 2013-11, Vol.503 (7477), p.487-492
• Main Authors: Heinz, S., Romanoski, C. E., Benner, C., Allison, K. A., Kaikkonen, M. U., Orozco, L. D., Glass, C. K.
• Format: Article
• Language: English
• Subjects: 631/208/200; 631/208/212/2019; 631/337/2019; Amino Acid Motifs - genetics; Animals; Base Sequence; Cell culture; Cell Lineage - genetics; Deoxyribonucleic acid; DNA; DNA methylation; DNA-Binding Proteins - metabolism; Enhancer Elements, Genetic - genetics; Gene Expression Regulation - genetics; Genes; Genetic diversity; Genetic variation; Genetic Variation - genetics; Genome-wide association studies; Genomes; Histones - chemistry; Histones - metabolism; Humanities and Social Sciences; Macrophages; Macrophages - metabolism; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Models, Biological; multidisciplinary; Mutation; Mutation - genetics; NF-kappa B - metabolism; Properties; Protein Binding; Reproducibility of Results; Science; Selection, Genetic - genetics; Transcription Factor RelA - metabolism; Transcription factors; Transcription Factors - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature12615

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. Naturally occurring genetic variation between inbred mouse strains is used as a mutagenesis strategy to investigate mechanisms responsible for the selection and function of cis -regulatory elements in macrophages; lineage-determining transcription factors are proposed to select enhancer-like regions in the genome in a collaborative fashion and facilitate the binding of signal-dependent factors. Genetic variation and the transcriptome The DNA sequence determinants that guide binding of lineage-determining transcription factors (LDTFs) are poorly understood. Here, Christopher Glass and colleagues exploit the naturally occurring genetic variation between inbred mouse strains as a mutagenesis strategy to investigate molecular mechanisms responsible for the selection and function of cis -regulatory elements in macrophages. By integrating data sets on transcription factor binding, histone marks and gene expression they develop a hierarchical model of LDTF function in selecting enhancer-like regions in a collaborative fashion and facilitating binding of signal-dependent factors. This model can be used to predict functional and potentially disease-causing regulatory variants.