OR41-5 Tissue-Specific Androgen Receptor Cistromes Identify Divergent Collaborating Factors in Mouse Prostate, Epididymis and Kidney

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR41-Sex Hormone Receptors in Development, Aging and Cancer: Omics Approaches
Monday, June 17, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:15 PM
Room 121 (Moscone Center)
Paivi Pihlajamaa*, Biswajyoti Sahu, Viljami Aittomaki, Lauri Lyly, Sampsa Hautaniemi and Olli A Janne*
University of Helsinki, Helsinki, Finland
Androgens regulate target gene expression in a tissue-specific manner via the androgen receptor (AR). We analyzed AR-binding sites (ARB) in three androgen-responsive murine tissues: in prostate and in kidney after a 2-h testosterone (T) exposure of castrated males, and in epididymis of intact males. ChIP-seq results revealed the presence of 10,171, 22,598, and 14,062 ARBs in prostate, epididymis, and kidney, respectively (two biological replicates, FDR<2%). Only 1,615 ARBs were shared by all three tissues, and at least one-half of the ARBs for each tissue were unique. De novo motif search revealed that a canonical androgen response element (ARE) sequence was enriched among the ChIP-seq peaks in all three tissues. However, enriched motifs for other cis-regulatory elements adjacent to ARBs unique to each tissue were significantly different: FoxA1 for prostate, Hnf4α for kidney and AP2 for epididymis. FoxA1 ChIP-seq from prostate and Hnf4α ChIP-seq from kidney revealed 18,759 and 16,539 binding sites, respectively. One third of prostate ARBs overlapped with the FoxA1 cistrome, and 50% of AR-binding events in kidney were shared with the Hnf4α cistrome, suggesting that FoxA1 in prostate and Hnf4α in kidney possess licensing functions for AR binding. One-third of the AR cistrome overlapped with that of AP2α in epididymis. Gene expression profiling from tissues of castrated male mice after a 3-day T or vehicle treatment identified 587 and 804 androgen-regulated transcripts (fold-change >1.5, p<0.05) in prostate and kidney, respectively. In agreement with the AR-binding events, most androgen-regulated transcripts were tissue-specific, as only 9% of up-regulated and 15% of down-regulated transcripts were common in prostate and kidney. Gene ontology categories related to metabolic processes and catalytic activity were enriched among up-regulated transcripts in kidney, and cell cycle- and nucleosome organization-related categories among up-regulated transcripts in prostate. Of note, ARBs were in many instances tissue-specific even for genes that were androgen-responsive in both tissues. In summary, in vivo androgen signaling in three androgen-responsive tissues – prostate, epididymis, and kidney – utilizes distinct chromatin AR-binding sites that appear to be specified by distinct pioneering (licensing) factors, which ultimately results in tissue-specific transcription programs in the AR pathway.

Nothing to Disclose: PP, BS, VA, LL, SH, OAJ

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