Genomic androgen receptor-occupied regions with different functions, defined by histone acetylation, coregulators and transcriptional capacity.
BACKGROUND
The androgen receptor (AR) is a steroid-activated transcription factor that binds at specific DNA locations and plays a key role in the etiology of prostate cancer. While numerous studies have identified a clear connection between AR binding and expression of target genes for a limited number of loci, high-throughput elucidation of these sites allows for a deeper understanding of the complexities of this process.


RESULTS
We have mapped 189 AR occupied regions (ARORs) and 1,388 histone H3 acetylation (AcH3) loci to a 3% continuous stretch of human genomic DNA using chromatin immunoprecipitation (ChIP) microarray analysis. Of 62 highly reproducible ARORs, 32 (52%) were also marked by AcH3. While the number of ARORs detected in prostate cancer cells exceeded the number of nearby DHT-responsive genes, the AcH3 mark defined a subclass of ARORs much more highly associated with such genes -- 12% of the genes flanking AcH3+ARORs were DHT-responsive, compared to only 1% of genes flanking AcH3-ARORs. Most ARORs contained enhancer activities as detected in luciferase reporter assays. Analysis of the AROR sequences, followed by site-directed ChIP, identified binding sites for AR transcriptional coregulators FoxA1, CEBPbeta, NFI and GATA2, which had diverse effects on endogenous AR target gene expression levels in siRNA knockout experiments.


CONCLUSIONS
We suggest that only some ARORs function under the given physiological conditions, utilizing diverse mechanisms. This diversity points to differential regulation of gene expression by the same transcription factor related to the chromatin structure.
Jia
Li
L
Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.
Berman
Benjamin P
BP
Jariwala
Unnati
U
Yan
Xiting
X
Cogan
Jon P
JP
Walters
Allison
A
Chen
Ting
T
Buchanan
Grant
G
Frenkel
Baruch
B
Coetzee
Gerhard A
GA
D000107:Acetylation; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics; D015894:Genome, Human; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008297:Male; D008954:Models, Biological; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D006657:Histones; D011944:Receptors, Androgen; D014157:Transcription Factors