NFI transcription factors interact with FOXA1 to regulate prostate-specific gene expression.

Grabowska MM, Elliott AD, DeGraff DJ, Anderson PD, Anumanthan G, Yamashita H, Sun Q, Friedman DB, Hachey DL, Yu X, Sheehan JH, Ahn JM, Raj GV, Piston DW, Gronostajski RM, Matusik RJ
Mol Endocrinol. 2014 28 (6): 949-64

PMID: 24801505 · PMCID: PMC4042066 · DOI:10.1210/me.2013-1213

Androgen receptor (AR) action throughout prostate development and in maintenance of the prostatic epithelium is partly controlled by interactions between AR and forkhead box (FOX) transcription factors, particularly FOXA1. We sought to identity additional FOXA1 binding partners that may mediate prostate-specific gene expression. Here we identify the nuclear factor I (NFI) family of transcription factors as novel FOXA1 binding proteins. All four family members (NFIA, NFIB, NFIC, and NFIX) can interact with FOXA1, and knockdown studies in androgen-dependent LNCaP cells determined that modulating expression of NFI family members results in changes in AR target gene expression. This effect is probably mediated by binding of NFI family members to AR target gene promoters, because chromatin immunoprecipitation (ChIP) studies found that NFIB bound to the prostate-specific antigen enhancer. Förster resonance energy transfer studies revealed that FOXA1 is capable of bringing AR and NFIX into proximity, indicating that FOXA1 facilitates the AR and NFI interaction by bridging the complex. To determine the extent to which NFI family members regulate AR/FOXA1 target genes, motif analysis of publicly available data for ChIP followed by sequencing was undertaken. This analysis revealed that 34.4% of peaks bound by AR and FOXA1 contain NFI binding sites. Validation of 8 of these peaks by ChIP revealed that NFI family members can bind 6 of these predicted genomic elements, and 4 of the 8 associated genes undergo gene expression changes as a result of individual NFI knockdown. These observations suggest that NFI regulation of FOXA1/AR action is a frequent event, with individual family members playing distinct roles in AR target gene expression.

MeSH Terms (18)

Androgen-Binding Protein Base Sequence Binding Sites Consensus Sequence Enhancer Elements, Genetic Gene Expression Regulation HeLa Cells Hepatocyte Nuclear Factor 3-alpha Humans Male NFI Transcription Factors Organ Specificity Promoter Regions, Genetic Prostate Protein Binding Protein Interaction Mapping Receptors, Androgen Transcription, Genetic

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