Pooled ChIP-Seq Links Variation in Transcription Factor Binding to Complex Disease Risk

Ashley K Tehranchi; Marsha Myrthil; Trevor Martin; Brian L Hie; David Golan; Hunter B Fraser

doi:10.1016/j.cell.2016.03.041

Pooled ChIP-Seq Links Variation in Transcription Factor Binding to Complex Disease Risk

Cell. 2016 Apr 21;165(3):730-41. doi: 10.1016/j.cell.2016.03.041. Epub 2016 Apr 14.

Authors

Ashley K Tehranchi¹, Marsha Myrthil², Trevor Martin¹, Brian L Hie³, David Golan⁴, Hunter B Fraser⁵

Affiliations

¹ Department of Biology, Stanford University, Stanford, CA 94305, USA.
² Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
³ Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
⁴ Department of Genetics, Stanford University, Stanford, CA 94305, USA; Department of Statistics, Stanford University, Stanford, CA 94305, USA.
⁵ Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: hbfraser@stanford.edu.

Abstract

Cis-regulatory elements such as transcription factor (TF) binding sites can be identified genome-wide, but it remains far more challenging to pinpoint genetic variants affecting TF binding. Here, we introduce a pooling-based approach to mapping quantitative trait loci (QTLs) for molecular-level traits. Applying this to five TFs and a histone modification, we mapped thousands of cis-acting QTLs, with over 25-fold lower cost compared to standard QTL mapping. We found that single genetic variants frequently affect binding of multiple TFs, and CTCF can recruit all five TFs to its binding sites. These QTLs often affect local chromatin and transcription but can also influence long-range chromosomal contacts, demonstrating a role for natural genetic variation in chromosomal architecture. Thousands of these QTLs have been implicated in genome-wide association studies, providing candidate molecular mechanisms for many disease risk loci and suggesting that TF binding variation may underlie a large fraction of human phenotypic variation.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Chromatin Immunoprecipitation / methods*
Genetic Predisposition to Disease
High-Throughput Nucleotide Sequencing / methods*
Histone Code
Humans
Polymorphism, Single Nucleotide*
Quantitative Trait Loci*
Sequence Analysis, DNA / methods*
Transcription Factors / metabolism*

Substances

Transcription Factors

Grants and funding

DP2 OD008456/OD/NIH HHS/United States