Abstract 930: Reprogramming the transcriptional response to hormone through functionally-distinct classes of gene enhancers in prostate cancer cells

Abstract

Abstract Mammalian genomes are populated with thousands of transcriptional enhancers that orchestrate cell type-specific gene expression programs; however, the potential that there are pre-established enhancers that permit alternative signal-dependent transcriptional responses has remained unexplored. Here we present evidence that cell lineage-specific factors, such as FoxA1, which contribute to the activation of cell-type specific enhancers by selectively favoring the recruitment of key regulated transcription factors such as the androgen receptor (AR) in prostate cancer cells, can simultaneously restrict these same factors from activating additional (alternative) pre-established but yet inactive enhancers, thus licensing specific signal-activated responses and restricting others. Importantly, these alternative hormonal responses are linked to distinct structural and functional classes of enhancers. Consequently, FoxA1 down-regulation, an unfavorable prognostic sign in some sets of advanced prostate tumors, causes a massive switch in AR binding from one functional enhancer class to another, which massively reprograms the hormonal response. The molecular basis for this switch lies in the release of FoxA1-mediated “restriction” of AR binding to the new enhancer class that requires no apparent nucleosome remodeling for their activation. Multiple global analyses of enhancer formation, structure, looping, and activation were combined to support these conclusions, including: H3K4me1/me3, H3K27ac, and H4K4ac mapping (ChIP-seq); nucleosomal H3K4me2 mapping (nucleosomal ChIP-seq); FoxA1, AR, p300, and MED12 mapping (ChIP-seq), also supported by the 3C assay; enhancer ncRNA or eRNAs generation analysis (GRO-seq); and gene expression analysis (microarray and GRO-seq). Together, these findings reveal a large repository of pre-determined enhancers in the human genome that can be dynamically tuned to induce alternative gene expression programs, which -we speculate- may underlie many sequential gene expression events in development or during cancer progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 930. doi:10.1158/1538-7445.AM2011-930