Closing the circadian negative feedback loop: FRQ-dependent clearance of WC-1 from the nucleus

Hong, Christian I.; Ruoff, Peter; Loros, Jennifer J.; Dunlap, Jay C.

doi:10.1101/gad.1706908

Cited by 64 publications

(82 citation statements)

References 36 publications

(65 reference statements)

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“…fragmented free-running behavior [103,104], supporting the critical role of Rev-erbs in generating robust rhythms. Furthermore, just as the slower additional NFL is more effective in PS models [59], the half-lives of activators are also considerably longer than those of repressors in mammals [121][122][123][124][125], Drosophila [126,127] and Neurospora [76]. Tight regulation of activator level via an additional NFL (Fig.…”

Section: Robust Designs Of Interlocked Transcriptional Feedback Loopsmentioning

confidence: 99%

Protein sequestration versus Hill‐type repression in circadian clock models

Kim¹

2016

IET syst. biol.

107

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Circadian (~24hr) clocks are self-sustained endogenous oscillators with which organisms keep track of daily and seasonal time. Circadian clocks frequently rely on interlocked transcriptionaltranslational feedback loops to generate rhythms that are robust against intrinsic and extrinsic perturbations. To investigate the dynamics and mechanisms of the intracellular feedback loops in circadian clocks, a number of mathematical models have been developed. The majority of the models use Hill functions to describe transcriptional repression in a way that is similar to the Goodwin model. Recently, a new class of models with protein sequestration-based repression has been introduced. Here, we discuss how this new class of models differs dramatically from those based on Hill-type repression in several fundamental aspects: conditions for rhythm generation, robust network designs and the periods of coupled oscillators. Consistently, these fundamental properties of circadian clocks also differ among Neurospora, Drosophila, and mammals depending on their key transcriptional repression mechanisms (Hill-type repression or protein sequestration). Based on both theoretical and experimental studies, this review highlights the importance of careful modeling of transcriptional repression mechanisms in molecular circadian clocks.

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Section: Robust Designs Of Interlocked Transcriptional Feedback Loopsmentioning

confidence: 99%

Protein sequestration versus Hill‐type repression in circadian clock models

Kim¹

2016

IET syst. biol.

107

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“…FRQ-FRH inhibits frq expression through a direct interaction with WCC that is mediated by WC-2 (7,8). FRQ undergoes phase-specific phosphorylation over the course of the day, and this phosphorylation controls regulated transport between the nucleus and cytoplasm, destabilization, and turnover (9)(10)(11)(12). In addition, there appears to be fine-tuned control of chromatin in both the activation and feedback inhibition phases of circadian oscillations (13)(14)(15)(16)(17).…”

Section: Dna Methylationmentioning

confidence: 99%

The frequency natural antisense transcript first promotes, then represses, frequency gene expression via facultative heterochromatin

Joska

Ruesch

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The circadian clock is controlled by a network of interconnected feedback loops that require histone modifications and chromatin remodeling. Long noncoding natural antisense transcripts (NATs) originate from Period in mammals and frequency (frq) in Neurospora. To understand the role of NATs in the clock, we put the frq antisense transcript qrf (frq spelled backwards) under the control of an inducible promoter. Replacing the endogenous qrf promoter altered heterochromatin formation and DNA methylation at frq. In addition, constitutive, low-level induction of qrf caused a dramatic effect on the endogenous rhythm and elevated circadian output. Surprisingly, even though qrf is needed for heterochromatic silencing, induction of qrf initially promoted frq gene expression by creating a more permissible local chromatin environment. The observation that antisense expression can initially promote sense gene expression before silencing via heterochromatin formation at convergent loci is also found when a NAT to hygromycin resistance gene is driven off the endogenous vivid (vvd) promoter in the Δvvd strain. Facultative heterochromatin silencing at frq functions in a parallel pathway to previously characterized VVDdependent silencing and is needed to establish the appropriate circadian phase. Thus, repression via dicer-independent siRNAmediated facultative heterochromatin is largely independent of, and occurs alongside, other feedback processes.circadian rhythm | natural antisense transcripts | heterochromatin | DNA methylation I n eukaryotes, metazoans, and vertebrates, the circadian rhythm requires timed chromatin remodeling and modifications to ensure the appropriate amplitude, period, and phase of clock gene expression. The need for chromatin regulation arises because the clock is predominantly controlled by a transcriptional negative feedback loop where transcriptional activators drive expression of negative elements that inhibit its own expression (1-3). In Neurospora crassa, the positive elements are the GATA type transcription factors White Collar-1 (WC-1) and WC-2 that form the White Collar complex (WCC) (4). The WCC drives expression of frequency (frq) that is translated with delays before it associates with FRQ-interacting RNA helicase (FRH) (5, 6). FRQ-FRH inhibits frq expression through a direct interaction with WCC that is mediated by WC-2 (7, 8). FRQ undergoes phase-specific phosphorylation over the course of the day, and this phosphorylation controls regulated transport between the nucleus and cytoplasm, destabilization, and turnover (9-12). In addition, there appears to be fine-tuned control of chromatin in both the activation and feedback inhibition phases of circadian oscillations (13)(14)(15)(16)(17).Recently, we reported that cytosines in the frq promoter are methylated (m 5 C) and proper regulation of the frq locus is needed for normal DNA methylation (13). The frq locus is composed of three transcripts: the frq gene encoding FRQ protein (6), a natural antisense transcript (NAT) qrf (frq spelled backwar...

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“…In light, VVD forms a rapidly exchanging dimer in solution, suggesting the possibility that the LOV domain of VVD could interact with other PAS domains, including those found in the WCC proteins (28)(29)(30). Cell fractionation studies have shown VVD to be exclusively localized in the cytosol (9), whereas most of the WCC is nuclear (9)(10)(11)(12), raising the question of how VVD communicates with the WCC to affect various WCC-mediated activities.…”

mentioning

confidence: 99%

“…The WHITE COLLAR (WC)-1 and WC-2 proteins control most light responses in Neurospora (7,8). WC-1, mainly localized in the nucleus (9)(10)(11)(12), is both a FAD-binding photoreceptor and a GATA zinc finger transcription factor (13,14). Through their PER-ARNT-SIM (PAS) domains (15)(16)(17), WC-1 and WC-2, another GATA zinc finger transcription factor, form the white collar complex (WCC).…”

mentioning

confidence: 99%

Physical interaction between VIVID and white collar complex regulates photoadaptation inNeurospora

Chen¹,

DeMay

Gladfelter

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

137

166

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Photoadaptation, the ability to attenuate a light response on prolonged light exposure while remaining sensitive to escalating changes in light intensity, is essential for organisms to decipher time information appropriately, yet the underlying molecular mechanisms are poorly understood. In Neurospora crassa, VIVID (VVD), a small LOV domain containing blue-light photoreceptor protein, affects photoadaptation for most if not all light-responsive genes. We report that there is a physical interaction between VVD and the white collar complex (WCC), the primary blue-light photoreceptor and the transcription factor complex that initiates light-regulated transcriptional responses in Neurospora. Using two previously characterized VVD mutants, we show that the level of interaction is correlated with the level of WCC repression in constant light and that even lightinsensitive VVD is sufficient partly to regulate photoadaptation in vivo. We provide evidence that a functional GFP-VVD fusion protein accumulates in the nucleus on light induction but that nuclear localization of VVD does not require light. Constitutively expressed VVD alone is sufficient to change the dynamics of photoadaptation. Thus, our results demonstrate a direct molecular connection between two of the most essential light signaling components in Neurospora, VVD and WCC, illuminating a previously uncharacterized process for light-sensitive eukaryotic cells.light | white collar-1 | white collar-2 | photoreceptor | LOV domain

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Closing the circadian negative feedback loop: FRQ-dependent clearance of WC-1 from the nucleus

Cited by 64 publications

References 36 publications

Protein sequestration versus Hill‐type repression in circadian clock models

Protein sequestration versus Hill‐type repression in circadian clock models

The frequency natural antisense transcript first promotes, then represses, frequency gene expression via facultative heterochromatin

Physical interaction between VIVID and white collar complex regulates photoadaptation inNeurospora

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