Cryptochrome 1 regulates the circadian clock through dynamic interactions with the BMAL1 C terminus

Xu, Hongwei; Gustafson, Chelsea L; Sammons, Patrick J.; Khan, Sanjoy K.; Parsley, Nicole C.; Ramanathan, Chidambaram; Lee, Hsiau‐Wei; Liu, Andrew C.; Partch, Carrie L.

doi:10.1038/nsmb.3018

Cited by 144 publications

(259 citation statements)

References 66 publications

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“…Thus, earlier appearance of the Cry1 in the pituitaries of hGH1 TG mice on the HFD may lead to repression of the Bmal1-Clock protein complex, which in turn signals an increase in Bmal1 production and increased RNA levels. A positive trend in Clock expression during the dark cycle by HFD was also observed, although it did not reach statistical significance (55).…”

Section: Discussionmentioning

confidence: 88%

“…These increases in Bmal1 and Cry1 transcript levels with a HFD have been reported previously (54) and may reflect a disrupted feedback system. Evidence suggests that a physical interaction between Cry1 and Bmal1 is responsible for switching Bmal1 from an activated to a repressive state (55). Thus, earlier appearance of the Cry1 in the pituitaries of hGH1 TG mice on the HFD may lead to repression of the Bmal1-Clock protein complex, which in turn signals an increase in Bmal1 production and increased RNA levels.…”

Section: Discussionmentioning

confidence: 99%

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Evidence for a Circadian Effect on the Reduction of Human Growth Hormone Gene Expression in Response to Excess Caloric Intake

Vakili¹,

Jin

Cattini

2016

Journal of Biological Chemistry

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Rhythmicity of biological functions is fundamental for optimal adaptations to environmental cues. Growth hormone (GH) is a major metabolic homeostatic factor that is secreted with a circadian pattern, but whether it is synthesized rhythmically is unknown. We used transgenic mice containing the human (h) GH gene (hGH1) locus to investigate the rhythmicity of hGH synthesis and secretion and to show that RNA and secreted protein levels oscillate over a 24-h cycle. Analysis of hGH1 promoter sequences revealed an enhancer motif (E-box) element that binds the circadian transcriptional machinery (Bmal1 and Clock). Furthermore, Bmal1/Clock were able to transactivate the hGH1 promoter, and mutation of this E-box element adversely affected basal activity after gene transfer. The ability of Bmal1 to bind the hGH1 promoter region containing the E-box element was confirmed in the hGH1 transgenic mouse pituitary in situ. Occupancy was reduced in mice fed a high fat diet during the light (inactive) stage of the daily cycle in mice and corresponded to a decrease in hGH1 RNA levels. The decreases in occupancy and RNA levels were not seen, however, during the dark (active) stage. A chromatin loop required for efficient postnatal hGH1 expression was negatively affected by the high fat diet in the light but not dark stage similar to the pattern observed with Bmal1 association with the promoter region. This is the first evidence that hGH synthesis follows a diurnal rhythm and of dynamic associations of the circadian machinery with a component of a chromosomal structure of the hGH1 locus that is essential for efficient expression.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Evidence for a Circadian Effect on the Reduction of Human Growth Hormone Gene Expression in Response to Excess Caloric Intake

Vakili¹,

Jin

Cattini

2016

Journal of Biological Chemistry

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“…Based on ChIP-Seq studies, these complexes appear to remodel or reform over time, evolving to a late repressive complex where CRY1 is bound to CLOCK:BMAL1 on DNA, apparently independently of PER (7).These findings suggest that cryptochromes can work both together and separately from PER to repress CLOCK:BMAL1 activity (8)(9)(10). We showed that tuning affinity of CRY1 for the transactivation domain (TAD) of BMAL1 controls circadian period by competing with the coactivator CBP/p300 (11). CRY1 also binds to CLOCK, although it is not yet understood how multivalent interactions with CLOCK: BMAL1 contribute to CRY1 function.…”

mentioning

confidence: 97%

“…The repressive activity of CRY1 is essential to generate circadian rhythms (13)(14)(15); one way that CRY1 does this is by binding the BMAL1 TAD to sequester it from coactivators (11,16). However, CRY1 has only moderate affinity (K d ∼1 μM) for the isolated TAD (11,17), suggesting that it makes at least one other interaction with CLOCK:BMAL1 that allows it to serve as a potent repressor when expressed to near stoichiometric levels (18). Previous studies suggest the CLOCK PAS-B domain is important for repression by CRY1 (11,19,20), but evidence for a direct interaction is lacking.…”

Section: Cry1mentioning

confidence: 99%

Formation of a repressive complex in the mammalian circadian clock is mediated by the secondary pocket of CRY1

Michael

Fribourgh

Chelliah

et al. 2017

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

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The basic helix–loop–helix PAS domain (bHLH-PAS) transcription factor CLOCK:BMAL1 (brain and muscle Arnt-like protein 1) sits at the core of the mammalian circadian transcription/translation feedback loop. Precise control of CLOCK:BMAL1 activity by coactivators and repressors establishes the ∼24-h periodicity of gene expression. Formation of a repressive complex, defined by the core clock proteins cryptochrome 1 (CRY1):CLOCK:BMAL1, plays an important role controlling the switch from repression to activation each day. Here we show that CRY1 binds directly to the PAS domain core of CLOCK:BMAL1, driven primarily by interaction with the CLOCK PAS-B domain. Integrative modeling and solution X-ray scattering studies unambiguously position a key loop of the CLOCK PAS-B domain in the secondary pocket of CRY1, analogous to the antenna chromophore-binding pocket of photolyase. CRY1 docks onto the transcription factor alongside the PAS domains, extending above the DNA-binding bHLH domain. Single point mutations at the interface on either CRY1 or CLOCK disrupt formation of the ternary complex, highlighting the importance of this interface for direct regulation of CLOCK:BMAL1 activity by CRY1.

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“…1d) appears to be responsible for transcriptional repression in Drosophila and mammals [77][78][79][80][81][82][83]. Specifically, in these organisms, repressors sequester activators in a 1:1 stoichiometric complex, which inhibits the transcriptional activity of activators.…”

Section: Introductionmentioning

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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Cryptochrome 1 regulates the circadian clock through dynamic interactions with the BMAL1 C terminus

Cited by 144 publications

References 66 publications

Evidence for a Circadian Effect on the Reduction of Human Growth Hormone Gene Expression in Response to Excess Caloric Intake

Evidence for a Circadian Effect on the Reduction of Human Growth Hormone Gene Expression in Response to Excess Caloric Intake

Formation of a repressive complex in the mammalian circadian clock is mediated by the secondary pocket of CRY1

Protein sequestration versus Hill‐type repression in circadian clock models

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