Publication Date:
2013-10-15
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994126/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994126/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Heinz, S -- Romanoski, C E -- Benner, C -- Allison, K A -- Kaikkonen, M U -- Orozco, L D -- Glass, C K -- 5T32DK007494/DK/NIDDK NIH HHS/ -- CA17390/CA/NCI NIH HHS/ -- DK063491/DK/NIDDK NIH HHS/ -- DK091183/DK/NIDDK NIH HHS/ -- P01 DK074868/DK/NIDDK NIH HHS/ -- P30 CA023100/CA/NCI NIH HHS/ -- P30 DK063491/DK/NIDDK NIH HHS/ -- R01 CA173903/CA/NCI NIH HHS/ -- R01 DK091183/DK/NIDDK NIH HHS/ -- T32 AR059033/AR/NIAMS NIH HHS/ -- England -- Nature. 2013 Nov 28;503(7477):487-92. doi: 10.1038/nature12615. Epub 2013 Oct 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, Mail Code 0651, La Jolla, California 92093, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24121437" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Motifs/genetics
;
Animals
;
Base Sequence
;
Cell Lineage/genetics
;
DNA-Binding Proteins/metabolism
;
Enhancer Elements, Genetic/*genetics
;
Gene Expression Regulation/*genetics
;
Genetic Variation/*genetics
;
Histones/chemistry/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
;
Selection, Genetic/*genetics
;
Transcription Factor RelA/metabolism
;
Transcription Factors/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
