FOXA1 is a 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. Continuing our endeavor to better understand TET1’s role in context of prostate cancer, we found that there exists a transcript isoform for TET1 in prostate cells, which has not been characterized before. Driven by an alternative promoter, the isoform lacks the first 2 exons of the full length gene but has an extra exon from the intronic region in front of exon 3, and is expressed more than 20-fold higher than full length. Functional experiments revealed that the short isoform (later referred to as TET1s) is important for regulating AR expression and thus AR signaling program, therefore making TET1s crucial for prostate cancer cell growth and survival.

Last modified

• 01/29/2019

Creator

• Yeqing (Angela) Yang

DOI

• https://doi.org/10.21985/N28M3B

Subject

• Driskill Graduate Training Program in Life Sciences

Keyword

• Prostate cancer
• TET1
• Epigenetics
• FOXA1

Date created

• 2017-01-01

Resource type

• Dissertation

Rights statement

• In Copyright