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Differential binding and co-binding pattern of FOXA1 and FOXA3 and their relation to H3K4me3 in HepG2 cells revealed by ChIP-seq

Mehdi Motallebipour17*, Adam Ameur28, Madhu Sudhan Reddy Bysani1, Kalicharan Patra19, Ola Wallerman1, Jonathan Mangion3, Melissa A Barker4, Kevin J McKernan5, Jan Komorowski26 and Claes Wadelius1*

Author Affiliations

1 Department of Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Dag Hammarskjölds väg 20, Uppsala SE-75185, Sweden

2 Linnaeus Centre for Bioinformatics, Uppsala University, Biomedical Center, Husargatan 3, Uppsala SE-75124, Sweden

3 Applied Biosystems UK, 120 Birchwood Boulevard, Warrington WA3 7QH, Cheshire, UK

4 Life Technologies, 850 Lincoln Centre Drive, Foster City, CA 94404, USA

5 Life Technologies, 500 Cummings Center, Suite 2400, Beverly, MA 01915, USA

6 Interdisciplinary Centre for Mathematical and Computer Modeling, Warsaw University, Krakowskie Przedmieœcie 26/28, Warszawa 00-927, Poland

7 Current address: MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK

8 Current address: Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjölds väg 20, Uppsala SE-75185, Sweden

9 Current address: Department of Development and Genetics, EBC, Uppsala University, Norbyvägen 18, Uppsala SE-75236, Sweden

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Genome Biology 2009, 10:R129  doi:10.1186/gb-2009-10-11-r129

Published: 17 November 2009

Abstract

Background

The forkhead box/winged helix family members FOXA1, FOXA2, and FOXA3 are of high importance in development and specification of the hepatic linage and the continued expression of liver-specific genes.

Results

Here, we present a genome-wide location analysis of FOXA1 and FOXA3 binding sites in HepG2 cells through chromatin immunoprecipitation with detection by sequencing (ChIP-seq) studies and compare these with our previous results on FOXA2. We found that these factors often bind close to each other in different combinations and consecutive immunoprecipitation of chromatin for one and then a second factor (ChIP-reChIP) shows that this occurs in the same cell and on the same DNA molecule, suggestive of molecular interactions. Using co-immunoprecipitation, we further show that FOXA2 interacts with both FOXA1 and FOXA3 in vivo, while FOXA1 and FOXA3 do not appear to interact. Additionally, we detected diverse patterns of trimethylation of lysine 4 on histone H3 (H3K4me3) at transcriptional start sites and directionality of this modification at FOXA binding sites. Using the sequence reads at polymorphic positions, we were able to predict allele specific binding for FOXA1, FOXA3, and H3K4me3. Finally, several SNPs associated with diseases and quantitative traits were located in the enriched regions.

Conclusions

We find that ChIP-seq can be used not only to create gene regulatory maps but also to predict molecular interactions and to inform on the mechanisms for common quantitative variation.