title: The Arcuate Estrogen-Regulated Transcriptome: Estrogen Response Element-Dependent and -Independent Signaling of ERα in Female Mice.
abstract: To influence energy homeostasis and reproduction, 17β-estradiol (E2) controls the arcuate nucleus (ARC) through multiple receptor-mediated mechanisms, but primarily via estrogen receptor (ER) α, which signals through both estrogen response element (ERE)-dependent and -independent mechanisms. To determine ERα-mediated, ERE-dependent, and ERE-independent E2 signaling in the ARC, we examined the differential regulation of the mouse arcuate transcriptome by E2 using three mice genotypes: (1) wild-type, (2) ERα knock-in/knockout (ERE-independent mechanisms), and (3) total ERα knockout (ERα-independent mechanisms). Females were ovariectomized and injected with oil or E2, and RNA sequencing on the ARC was used to identify E2-regulated genes in each genotype. Our results show that E2 regulates numerous genes involved in cell signaling, cytoskeleton structure, inflammation, neurotransmission, neuropeptide production, and transcription. Furthermore, ERE-independent signaling regulates ARC genes expressed in kisspeptin neurons and transcription factors that control the hypothalamic/pituitary/gonadal axis. Interestingly, a few genes involved in mitochondrial oxidative respiration were regulated by E2 through ERα-independent signaling. A comparison within oil- and E2-treated females across the three genotypes suggests that genes involved in cell growth and proliferation, extracellular matrices, neuropeptides, receptors, and transcription are differentially expressed across the genotypes. Comparing with previously published chromatin immunoprecipitation sequencing analysis, we found that ERE-independent regulation in the ARC is mainly mediated by tethering of ERα, which is consistent with previous findings. We conclude that the mouse arcuate estrogen-regulated transcriptome is regulated by multiple receptor-mediated mechanisms to modulate the central control of energy homeostasis and reproduction, including novel E2-responsive pathways.
authors.affiliation: Department of Animal Sciences and Program in Endocrinology and Animal Biosciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Yang
authors.affiliation: Department of Animal Sciences and Program in Endocrinology and Animal Biosciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey.
authors.forename: Hillary
authors.initials: H
authors.lastname: Stires
authors.affiliation: Department of Animal Sciences and Program in Endocrinology and Animal Biosciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey.
authors.forename: William J
authors.initials: WJ
authors.lastname: Belden
authors.affiliation: Department of Animal Sciences and Program in Endocrinology and Animal Biosciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey.
authors.forename: Troy A
authors.initials: TA
authors.lastname: Roepke
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism*; D004958:Estradiol / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009479:Neuropeptides / Q000378:metabolism; D016133:Polymerase Chain Reaction; D020218:Response Elements; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D047628:Estrogen Receptor alpha; D009479:Neuropeptides; D004958:Estradiol