title: Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA.
abstract: Mammalian genomes are populated with thousands of transcriptional enhancers that orchestrate cell-type-specific gene expression programs, but how those enhancers are exploited to institute alternative, signal-dependent transcriptional responses remains poorly understood. Here we present evidence that cell-lineage-specific factors, such as FoxA1, can simultaneously facilitate and restrict key regulated transcription factors, exemplified by the androgen receptor (AR), to act on structurally and functionally distinct classes of enhancer. Consequently, FoxA1 downregulation, an unfavourable prognostic sign in certain advanced prostate tumours, triggers dramatic reprogramming of the hormonal response by causing a massive switch in AR binding to a distinct cohort of pre-established enhancers. These enhancers are functional, as evidenced by the production of enhancer-templated non-coding RNA (eRNA) based on global nuclear run-on sequencing (GRO-seq) analysis, with a unique class apparently requiring no nucleosome remodelling to induce specific enhancer-promoter looping and gene activation. GRO-seq data also suggest that liganded AR induces both transcription initiation and elongation. Together, these findings reveal a large repository of active enhancers that can be dynamically tuned to elicit alternative gene expression programs, which may underlie many sequential gene expression events in development, cell differentiation and disease progression.
authors.affiliation: Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0651, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.forename: Ivan
authors.initials: I
authors.lastname: Garcia-Bassets
authors.forename: Chris
authors.initials: C
authors.lastname: Benner
authors.forename: Wenbo
authors.initials: W
authors.lastname: Li
authors.forename: Xue
authors.initials: X
authors.lastname: Su
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhou
authors.forename: Jinsong
authors.initials: J
authors.lastname: Qiu
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.forename: Minna U
authors.initials: MU
authors.lastname: Kaikkonen
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Ohgi
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Fu
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D019070:Cell Lineage; D013196:Dihydrotestosterone / Q000494:pharmacology; D015536:Down-Regulation; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D015894:Genome, Human / Q000235:genetics; D057809:HEK293 Cells; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007610:Kallikreins; D008297:Male; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D022661:RNA, Untranslated / Q000235:genetics*; D011944:Receptors, Androgen / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D006657:Histones; D034741:RNA, Small Interfering; D022661:RNA, Untranslated; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen