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Nucleic Acids Res. 2016 Sep 30;44(17):8153-64. doi: 10.1093/nar/gkw498. Epub 2016 Jun 1.

FOXA1 potentiates lineage-specific enhancer activation through modulating TET1 expression and function.

Author information

1
Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
2
Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, the University of Chicago, Chicago, IL 60637, USA.
3
Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, the University of Chicago, Chicago, IL 60637, USA Howard Hughes Medical Institute, the University of Chicago, Chicago, IL 60637, USA.
4
Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA jindan-yu@northwestern.edu.

Abstract

Forkhead box A1 (FOXA1) is an FKHD family protein that plays pioneering roles in lineage-specific enhancer activation and gene transcription. Through genome-wide location analyses, here we show that FOXA1 expression and occupancy are, in turn, required for the maintenance of these epigenetic signatures, namely DNA hypomethylation and histone 3 lysine 4 methylation. Mechanistically, this involves TET1, a 5-methylcytosine dioxygenase. We found that FOXA1 induces TET1 expression via direct binding to its cis-regulatory elements. Further, FOXA1 physically interacts with the TET1 protein through its CXXC domain. TET1 thus co-occupies FOXA1-dependent enhancers and mediates local DNA demethylation and concomitant histone 3 lysine 4 methylation, further potentiating FOXA1 recruitment. Consequently, FOXA1 binding events are markedly reduced following TET1 depletion. Together, our results suggest that FOXA1 is not only able to recognize but also remodel the epigenetic signatures at lineage-specific enhancers, which is mediated, at least in part, by a feed-forward regulatory loop between FOXA1 and TET1.

PMID:
27257062
PMCID:
PMC5041455
DOI:
10.1093/nar/gkw498
[Indexed for MEDLINE]
Free PMC Article

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