Effect of natural genetic variation on enhancer selection and function.

TitleEffect of natural genetic variation on enhancer selection and function.
Publication TypeJournal Article
Year of Publication2013
AuthorsHeinz S, Romanoski CE, Benner C, Allison KA, Kaikkonen MU, Orozco LD, Glass CK
JournalNature
Volume503
Issue7477
Pagination487-92
Date Published2013 Nov 28
ISSN1476-4687
KeywordsAmino Acid Motifs, Animals, Base Sequence, Cell Lineage, DNA-Binding Proteins, Enhancer Elements, Genetic, Gene Expression Regulation, Genetic Variation, Histones, Macrophages, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Models, Biological, Mutation, NF-kappa B, Protein Binding, Reproducibility of Results, Selection, Genetic, Transcription Factor RelA, Transcription Factors
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.

DOI10.1038/nature12615
Alternate JournalNature
PubMed ID24121437
PubMed Central IDPMC3994126
Grant ListP01 DK074868 / DK / NIDDK NIH HHS / United States
R01 CA173903 / CA / NCI NIH HHS / United States
T32 AR059033 / AR / NIAMS NIH HHS / United States
CA17390 / CA / NCI NIH HHS / United States
R01 DK091183 / DK / NIDDK NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
P30 CA023100 / CA / NCI NIH HHS / United States
5T32DK007494 / DK / NIDDK NIH HHS / United States
DK091183 / DK / NIDDK NIH HHS / United States
T32 DK007494 / DK / NIDDK NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
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