Biomedical subjects

Michelle Brewer

Publications and source records attributed to Michelle Brewer.

4 recordsLinked to original sources

PubMed2006

Elovl3: a model gene to dissect homeostatic links between the circadian clock and nutritional status.

The ELOVL3 protein is a very long-chain fatty acid elongase found in liver, skin, and brown adipose tissues. Circadian expression of the Elovl3 gene in the liver is perturbed in mutant CLOCK mice but persists in mice with severe hepatic dysfunction. A reliance on an intact clock, combined with the refractoriness to liver decompensation and the finding of a robust sexually dimorphic pattern of expression, evince a particularly complex mode of transcriptional control. The Elovl3 gene upstream region was repressed by RevErbalpha and activated by sterol-regulatory element binding protein-1 (SREBP1) transcription factors. We propose that the temporal coordination of RevErbalpha and SREBP1 activities integrates clock and nutrition signals to drive a subset of oscillatory transcripts in the liver. Proteolytic activation of SREBP1 is circadian in the liver, and because the cycle of SREBP1 activation was reversed after restricting meals to the inactive phase of the day, this factor could serve as an acute sensor of nutritional state. SREBP1 regulates many known lipogenic and cholesterogenic circadian genes; hence, our results could explain how feeding can override brain-derived entraining signals in the liver. This mechanism would permit a rapid adjustment in the sequence of key aspects of the absorptive and postabsorptive phases in the liver.

Acetyltransferases↗

PubMed2006

Modulation of BMAL/CLOCK/E-Box complex activity by a CT-rich cis-acting element.

The interaction between the BMAL1/CLOCK transcription factor and the cis-acting element known as the E-Box is a key event in the regulation of clock and clock-controlled gene expression. However, the fact that the ubiquitous E-Box element sits at the center of a presumably highly discriminating control system generates a certain level of puzzlement. Widely spread E-Boxes with a generic sequence CANNTG have been associated with expression of genes involved in a host of disparate biological processes, including the orchestration of circadian physiology. The intriguing specificity of this short DNA consensus element begs the hypothesis that its actual circadian properties might be encoded elsewhere, e.g., other factors or adjacent sequences. In a previous study, we found evidence that a short sequence in the mouse arginine vasopressin (AVP) proximal promoter has the ability to confer robust BMAL1/CLOCK responsiveness onto an adjacent E-Box. Here, we report the systematic analysis of this element. Our findings further define the determining features and sequence boundaries of this element, establish the effect of the photoperiod upon its interacting protein(s), and suggest that its cognate binding activity might be modulated by Zn2+ in a peripheral oscillator.

3T3 Cells↗

PubMed2005

SREBP-1 as a transcriptional integrator of circadian and nutritional cues in the liver.

The act of feeding in mammals can generate such powerful cues for peripheral organs that, under certain conditions, they can override the entraining signals coming from the clock in the brain. Restricting the feeding time to the inactivity period, for example, can completely and quickly reverse the rhythms of gene expression in the liver. This manipulation does not affect the central oscillator in the suprachiasmatic nucleus, which is phase-locked to the light-dark cycle, but does release the peripheral oscillations in the liver from central control. It seems reasonable to predict the existence of one or more immediate response systems designed to sense the need to acutely reverse the sequence of absorptive and postabsorptive phases in the liver. In this study, the authors monitored the posttranslational activation of the sterol response element binding proteins from a circadian point of view to evaluate the role they might play in the circadian organization of the liver transcriptome as well as in the reversal of hepatic physiology that accompanies diurnal restricted feeding. This study highlights a possible direct link between the immediate effects of food consumption on the level of key membrane and humoral factors and the expression status of a set of coordinately regulated target genes in the liver.

Animals↗

PubMed2002

Circadian Transcription. Thinking outside the E-Box.

The E-Box is a widely used DNA control element. Despite its brevity and broad distribution the E-Box is a remarkably versatile sequence that affects many different genetic programs, including proliferation, differentiation, tissue-specific responses, and cell death. The circadian clock is one of the latest pathways shown to employ this element. In this context, E-Boxes are likely to play a key role in establishing the robust waves of gene expression characteristic of circadian transcription. The regulatory flexibility of the E-Box hinges on the sequence ambiguity allowed at its core, the strong influence of the surrounding sequences, and the recruitment of spatially and temporally regulated E-Box-binding factors. Therefore, understanding how a particular E-Box can accomplish a specific task entails the identification and systematic analysis of these cis- and trans-acting E-Box modifiers. In the present study we compared the E-Box-containing minimal promoters of vasopressin and cyclin B1, two genes that can respond to the transcriptional oscillators driving the circadian clock and cell cycle, respectively. Results of this comparison will help elucidate the manner in which discreet DNA modules associate to either augment or restrain the activation of potential circadian E-Boxes in response to competing regulatory signals.

3T3 Cells↗