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

Magdalena M. Grabowska, Amicia D. Elliott, David Degraff, Philip D. Anderson, Govindaraj Anumanthan, Hironobu Yamashita, Qian Sun, David B. Friedman, David L. Hachey, Xiuping Yu, Jonathan H. Sheehan, Jung Mo Ahn, Ganesh V. Raj, David W. Piston, Richard M. Gronostajski, Robert J. Matusik

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

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 familymemberscan bind 6of 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.

Original languageEnglish (US)
Pages (from-to)949-964
Number of pages16
JournalMolecular Endocrinology
Volume28
Issue number6
DOIs
StatePublished - Jan 1 2014

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NFI Transcription Factors
Androgen Receptors
Prostate
Transcription Factors
Gene Expression
Chromatin Immunoprecipitation
Genes
Forkhead Transcription Factors
Energy Transfer
Prostate-Specific Antigen
Androgens
Carrier Proteins
Epithelium
Binding Sites
Maintenance

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Endocrinology

Cite this

Grabowska, M. M., Elliott, A. D., Degraff, D., Anderson, P. D., Anumanthan, G., Yamashita, H., ... Matusik, R. J. (2014). NFI transcription factors interact with FOXA1 to regulate prostate-specific gene expression. Molecular Endocrinology, 28(6), 949-964. https://doi.org/10.1210/me.2013-1213
Grabowska, Magdalena M. ; Elliott, Amicia D. ; Degraff, David ; Anderson, Philip D. ; Anumanthan, Govindaraj ; Yamashita, Hironobu ; Sun, Qian ; Friedman, David B. ; Hachey, David L. ; Yu, Xiuping ; Sheehan, Jonathan H. ; Ahn, Jung Mo ; Raj, Ganesh V. ; Piston, David W. ; Gronostajski, Richard M. ; Matusik, Robert J. / NFI transcription factors interact with FOXA1 to regulate prostate-specific gene expression. In: Molecular Endocrinology. 2014 ; Vol. 28, No. 6. pp. 949-964.
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Grabowska, MM, Elliott, AD, Degraff, D, 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 2014, 'NFI transcription factors interact with FOXA1 to regulate prostate-specific gene expression', Molecular Endocrinology, vol. 28, no. 6, pp. 949-964. https://doi.org/10.1210/me.2013-1213

NFI transcription factors interact with FOXA1 to regulate prostate-specific gene expression. / Grabowska, Magdalena M.; Elliott, Amicia D.; Degraff, David; Anderson, Philip D.; Anumanthan, Govindaraj; Yamashita, Hironobu; Sun, Qian; Friedman, David B.; Hachey, David L.; Yu, Xiuping; Sheehan, Jonathan H.; Ahn, Jung Mo; Raj, Ganesh V.; Piston, David W.; Gronostajski, Richard M.; Matusik, Robert J.

In: Molecular Endocrinology, Vol. 28, No. 6, 01.01.2014, p. 949-964.

Research output: Contribution to journalArticle

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T1 - NFI transcription factors interact with FOXA1 to regulate prostate-specific gene expression

AU - Grabowska, Magdalena M.

AU - Elliott, Amicia D.

AU - Degraff, David

AU - Anderson, Philip D.

AU - Anumanthan, Govindaraj

AU - Yamashita, Hironobu

AU - Sun, Qian

AU - Friedman, David B.

AU - Hachey, David L.

AU - Yu, Xiuping

AU - Sheehan, Jonathan H.

AU - Ahn, Jung Mo

AU - Raj, Ganesh V.

AU - Piston, David W.

AU - Gronostajski, Richard M.

AU - Matusik, Robert J.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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 familymemberscan bind 6of 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.

AB - 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 familymemberscan bind 6of 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.

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