Biology subjects

DeBruyne, J.

Publications and source records attributed to DeBruyne, J..

4 recordsLinked to original sources

bioRxiv2026

Remodeling of the hepatic circadian transcriptome across the estrous cycle

The circadian clock system drives rhythms in gene expression, tailoring an organism's behavior and physiology to the ~24-hour day-night environmental cycle. The mechanisms underlying this system are believed to be largely the same between adult males and females, but recent findings are starting to challenge this notion. Menstrual/estrous cycles (e-cycles) in females modulate a variety of circadian-controlled behaviors, but how they may interact with rhythmicity at the system level are an unknown but vital dimension in circadian biology in females. To start bridging this gap, we explored the circadian transcriptome of the mouse liver across the four phases of the free-running e-cycle. Much to our surprise, we found that the e-cycle imposes a ~4-day rhythm in the 24-hour rhythmicity of a considerable proportion of the circadian transcriptome, with the largest differences in rhythmicity occurring between pre- and post-ovulation phases. These differences also appear highly time-of-day dependent, and gene promotor analysis suggests that both e-cycle and sex dependent rhythmicity may be due to relatively simplistic mechanisms, possibly involving the action of core circadian transcription factors on output genes. Taken together, this study establishes that the estrous cycle modulates circadian gene expression in the liver, suggesting that circadian system has evolved specific mechanisms tailored to the different needs of males and females in their normal daily environments.

Systems Biology↗

bioRxiv2023

Environmental circadian disruption re-programs liver circadian gene expression

Circadian gene expression is fundamental to the establishment and functions of the circadian clock, a cell-autonomous and evolutionary-conserved timing system. Yet, how it is affected by environmental-circadian disruption (ECD) such as shiftwork and jetlag, which impact millions of people worldwide, are ill-defined. Here, we provided the first comprehensive description of liver circadian gene expression under normal and after ECD conditions. We found that post-transcription and post-translation processes are dominant contributors to whole-cell or nuclear circadian proteome, respectively. Furthermore, rhythmicity of 64% transcriptome, 98% whole-cell proteome and 95% nuclear proteome is re-written by ECD. The re-writing, which is associated with changes of circadian cis-regulatory elements, RNA-processing and protein trafficking, diminishes circadian regulation of fat and carbohydrate metabolism and persists after one week of ECD-recovery. One-Sentence SummaryEnvironmental-circadian disruption re-writes the circadian gene expression process which persists after one week of recovery.

molecular biology↗

bioRxiv2023

Lysine-independent ubiquitination and degradation of REV-ERBα involves a bi-functional degradation control sequence at its N-terminus

REV-ERB and REV-ERB{beta} proteins play crucial roles in linking the circadian system to overt daily rhythms in mammalian physiology and behavior. In most tissues, REV-ERB protein robustly cycles such that it is detected only within a tight interval of 4-6 hours each day, suggesting both its synthesis and degradation are tightly controlled. Several ubiquitin ligases are known to drive REV-ERB degradation, but how they interact with REV-ERB and which lysine residues they ubiquitinate to promote degradation are unknown. In this study, we attempted to identify both ubiquitin-ligase-binding and ubiquitination sites within REV-ERB required for its degradation. Surprisingly, mutating all lysine residues, the common sites for ubiquitin conjugation, in REV-ERB to arginines (K20R), did very little to impair its degradation in cells. K20R were degraded much faster by co-expression of two E3 ligases, SIAH2 or SPSB4, suggesting possible N-terminal ubiquitination. To explore this, we examined if small deletions at the N-terminus of REV-ERB would alter its degradation. Interestingly, deletion of amino acid (AA) residues 2 to 9 (delAA2-9) clearly resulted in a less stable REV-ERB. We found that it was the length (i.e. 8 AA), and not the specific sequence, that confers stability in this region. Simultaneously, we also mapped the interaction site of the E3 ligase SPSB4 to this same region, specifically requiring AA4-9 of REV-ERB. Thus, the first 9 AA of REV-ERB has two opposing roles in regulating REV-ERB turnover. Further, deleting eight additional AAs (delAA2-17) from the N-terminus strongly prevents REV-ERB degradation. Combined, these results suggest that complex interactions within the first 25AAs potentially act as an endogenous switch that allows REV-ERB to exist in a stabilized conformation in order to accumulate at one time of day, but then rapidly shifts to a destabilized form, to enhance its removal at the end of its daily cycle.

molecular biology↗

bioRxiv2020

A novel female-specific circadian clock mechanism regulating metabolism

Circadian clocks enable organisms to predict and align their behaviors and physiologies to constant daily day-night environmental cycle. Because the ubiquitin ligase Siah2 has been identified as a potential regulator of circadian clock function in cultured cells, we have used Siah2-deficient mice to examine its function in vivo. Our experiments demonstrate a striking and unexpected sexually dimorphic effect of Siah2 deficiency on the regulation of rhythmically expressed genes. The absence of Siah2 in females, but not in males, altered the expression of core circadian clock genes and drastically remodeled the rhythmic hepatic transcriptome. Siah2 loss, only in females, increased the expression of 100s of genes selectively at mid-day, resulting in a >50% increase in the number of rhythmically expressed genes, and shifted the expression of 100s of other genes from a mid-night peak, to a mid-day peak. The combined result is a near inversion of overall rhythmicity in gene expression selectively in Siah2-deficient females. This dramatic reorganization created a substantial misalignment between rhythmic liver functions and feeding/behavioral rhythms, and consequently disrupted daily patterns of lipid/lipoprotein metabolism and metabolic responses to high-fat diet. Collectively, our results suggest that Siah2 is part of a female-specific circadian mechanism important for maintaining metabolic homeostasis and may play a key role in establishing sexual dimorphisms in metabolism, and broadly reveal that circadian clocks may drive rhythms using novel sex-specific transcriptional pathways.

physiology↗