Effect of natural genetic variation on enhancer selection and function

S. Heinz, C. E. Romanoski, C. Benner, K. A. Allison, M. U. Kaikkonen, L. D. Orozco, C. K. Glass

Research output: Contribution to journalArticlepeer-review

223 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)487-492
Number of pages6
JournalNature
Volume503
Issue number7477
DOIs
StatePublished - 2013
Externally publishedYes

ASJC Scopus subject areas

  • General

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