The Paralogous Krüppel-like Factors 9 and 13 Regulate the Mammalian Cellular Circadian Clock Output GeneDbp
| Autor: | Robert J. Denver, José Ávila-Mendoza, Joseph R. Knoedler, Arasakumar Subramani |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Transcription Genetic Physiology Circadian clock Kruppel-Like Transcription Factors CLOCK Proteins Cell Cycle Proteins Biology Article Cell Line Gene Knockout Techniques Mice 03 medical and health sciences 0302 clinical medicine Transcription (biology) Circadian Clocks Physiology (medical) Animals Circadian rhythm Mice Knockout Zinc finger transcription factor Circadian Rhythm Chromatin Cell biology DNA-Binding Proteins Repressor Proteins PER3 KLF9 030104 developmental biology Gene Expression Regulation CRISPR-Cas Systems 030217 neurology & neurosurgery Transcription Factors PER1 |
| Zdroj: | J Biol Rhythms |
| ISSN: | 1552-4531 0748-7304 |
| DOI: | 10.1177/0748730420913205 |
| Popis: | An intricate transcription-translation feedback loop (TTFL) governs cellular circadian rhythms in mammals. Here, we report that the zinc finger transcription factor Krüppel-like factor 9 (KLF9) is regulated by this TTFL, it associates in chromatin at the core circadian clock and clock-output genes, and it acts to modulate transcription of the clock-output gene Dbp. Our earlier genome-wide analysis of the mouse hippocampus-derived cell line HT22 showed that KLF9 associates in chromatin with Per1, Per3, Dbp, Tef, Bhlhe40, Bhlhe41, Nr1d1, and Nr1d2. Of the 3514 KLF9 peaks identified in HT22 cells, 1028 contain E-box sequences to which the transcriptional activators CLOCK and BMAL1 may bind, a frequency significantly greater than expected by chance. Klf9 mRNA showed circadian oscillation in synchronized HT22 cells, mouse hippocampus, and liver. At the clock-output gene Dbp, KLF9 exhibited circadian rhythmicity in its association in chromatin in HT22 cells and hippocampus. Forced expression of KLF9 in HT22 cells repressed basal Dbp transcription and strongly inhibited CLOCK+BMAL1-dependent transcriptional activation of a transfected Dbp reporter. Mutational analysis showed that this action of KLF9 depended on 2 intact KLF9-binding motifs within the Dbp locus that are in close proximity to E-boxes. Knockout of Klf9 or the paralogous gene Klf13 using CRISPR/Cas9 genome editing in HT22 cells had no effect on Dbp expression, but combined knockout of both genes strongly impaired circadian Dbp mRNA oscillation. Like KLF9, KLF13 also showed association in chromatin with clock- and clock-output genes, and forced expression of KLF13 inhibited the actions of CLOCK+BMAL1 on Dbp transcription. Our results suggest novel and partly overlapping roles for KLF9 and KLF13 in modulating cellular circadian clock output by a mechanism involving direct interaction with the core TTFL. |
| Databáze: | OpenAIRE |
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