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.
|Number of pages||12|
|Journal||Nucleic Acids Research|
|State||Published - Sep 30 2016|
Bibliographical noteFunding Information:
U.S. Department of Defense [W81XWH-13-1-0319 to J.Y., in part]; American Cancer Society Research Scholar Award [RSG-12-085-01 to J.Y.]; National Institutes of Health [R01HG006827 to C.H.]; Howard Hughes Medical Institute (to C.H.); NIH/NCI training grant [T32 CA09560 to Y.A.Y., in part]; NIH Training Program in Oncogenesis and Developmental Biology [T32 CA080621 to J.K., in part]. Funding for open access charge: National Institutes of Health [R01-CA172384 to J.Y.]. Conflict of interest statement. None declared.
© 2016 The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.
ASJC Scopus subject areas