Deciphering the Regulatory Logic of an Ancient, Ultraconserved Nuclear Receptor Enhancer Module
| Autor: | Yasuhiro Kyono, Joseph R. Knoedler, Laurent M. Sachs, Xiaoan Ruan, Ronald M. Bonett, Robert J. Denver, Pia Bagamasbad, Yijun Ruan, Samhitha Raj, Nicolas Buisine |
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| Rok vydání: | 2015 |
| Předmět: |
Transcriptional Activation
Xenopus Kruppel-Like Transcription Factors Receptors Cytoplasmic and Nuclear RNA polymerase II Conserved sequence Evolution Molecular Histones Transactivation Receptors Glucocorticoid Endocrinology Animals RNA Messenger Enhancer Base Pairing Molecular Biology Conserved Sequence Original Research Regulation of gene expression Zinc finger transcription factor Base Sequence biology Brain Acetylation General Medicine Molecular biology Chromatin Cortisone Mice Inbred C57BL KLF9 Enhancer Elements Genetic Gene Expression Regulation Nuclear receptor Genetic Loci Gene Knockdown Techniques Mutagenesis Site-Directed biology.protein Triiodothyronine RNA Long Noncoding RNA Polymerase II Protein Binding |
| Zdroj: | Molecular Endocrinology. 29:856-872 |
| ISSN: | 1944-9917 0888-8809 |
| Popis: | Cooperative, synergistic gene regulation by nuclear hormone receptors can increase sensitivity and amplify cellular responses to hormones. We investigated thyroid hormone (TH) and glucocorticoid (GC) synergy on the Krüppel-like factor 9 (Klf9) gene, which codes for a zinc finger transcription factor involved in development and homeostasis of diverse tissues. We identified regions of the Xenopus and mouse Klf9 genes 5–6 kb upstream of the transcription start sites that supported synergistic transactivation by TH plus GC. Within these regions, we found an orthologous sequence of approximately 180 bp that is highly conserved among tetrapods, but absent in other chordates, and possesses chromatin marks characteristic of an enhancer element. The Xenopus and mouse approximately 180-bp DNA element conferred synergistic transactivation by hormones in transient transfection assays, so we designate this the Klf9 synergy module (KSM). We identified binding sites within the mouse KSM for TH receptor, GC receptor, and nuclear factor κB. TH strongly increased recruitment of liganded GC receptor and serine 5 phosphorylated (initiating) RNA polymerase II to chromatin at the KSM, suggesting a mechanism for transcriptional synergy. The KSM is transcribed to generate long noncoding RNAs, which are also synergistically induced by combined hormone treatment, and the KSM interacts with the Klf9 promoter and a far upstream region through chromosomal looping. Our findings support that the KSM plays a central role in hormone regulation of vertebrate Klf9 genes, it evolved in the tetrapod lineage, and has been maintained by strong stabilizing selection. |
| Databáze: | OpenAIRE |
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