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Nucleic Acids Res. 2018 Jun 20;46(11):5470-5486. doi: 10.1093/nar/gky259.

DNA-mediated dimerization on a compact sequence signature controls enhancer engagement and regulation by FOXA1.

Author information

1
CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences and Guangzhou Medical University, Guangzhou 511436, China.
2
Genome Regulation Laboratory, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
3
University of Chinese Academy of Sciences, Beijing 100049, China.
4
Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
5
Faculty of Mathematics, Informatics and Mechanics, University of Warsaw, 02-097 Warszawa, Poland.
6
Genome Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
7
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 75 Ames St., Cambridge MA 02142, USA.
8
Computational Structural Biology Laboratory, Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, Münster 48149, Germany.
9
Center for Multiscale Theory and Computation, Westfälische Wilhelms University, 48149 Münster, Germany.
10
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.

Abstract

FOXA1 is a transcription factor capable to bind silenced chromatin to direct context-dependent cell fate conversion. Here, we demonstrate that a compact palindromic DNA element (termed 'DIV' for its diverging half-sites) induces the homodimerization of FOXA1 with strongly positive cooperativity. Alternative structural models are consistent with either an indirect DNA-mediated cooperativity or a direct protein-protein interaction. The cooperative homodimer formation is strictly constrained by precise half-site spacing. Re-analysis of chromatin immunoprecipitation sequencing data indicates that the DIV is effectively targeted by FOXA1 in the context of chromatin. Reporter assays show that FOXA1-dependent transcriptional activity declines when homodimeric binding is disrupted. In response to phosphatidylinositol-3 kinase inhibition DIV sites pre-bound by FOXA1 such as at the PVT1/MYC locus exhibit a strong increase in accessibility suggesting a role of the DIV configuration in the chromatin closed-open dynamics. Moreover, several disease-associated single nucleotide polymorphisms map to DIV elements and show allelic differences in FOXA1 homodimerization, reporter gene expression and are annotated as quantitative trait loci. This includes the rs541455835 variant at the MAPT locus encoding the Tau protein associated with Parkinson's disease. Collectively, the DIV guides chromatin engagement and regulation by FOXA1 and its perturbation could be linked to disease etiologies.

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