Erin L. McDearmon

Bio: Erin L. McDearmon is an academic researcher from Northwestern University. The author has contributed to research in topics: Circadian rhythm & Transcriptome. The author has an hindex of 9, co-authored 11 publications receiving 4723 citations. Previous affiliations of Erin L. McDearmon include Howard Hughes Medical Institute.

Obesity and Metabolic Syndrome in Circadian Clock Mutant Mice

Abstract: The CLOCK transcription factor is a key component of the molecular circadian clock within pacemaker neurons of the hypothalamic suprachiasmatic nucleus. We found that homozygous Clock mutant mice have a greatly attenuated diurnal feeding rhythm, are hyperphagic and obese, and develop a metabolic syndrome of hyperleptinemia, hyperlipidemia, hepatic steatosis, hyperglycemia, and hypoinsulinemia. Expression of transcripts encoding selected hypothalamic peptides associated with energy balance was attenuated in the Clock mutant mice. These results suggest that the circadian clock gene network plays an important role in mammalian energy balance.

The Genetics of Mammalian Circadian Order and Disorder: Implications for Physiology and Disease

Abstract: Circadian cycles affect a variety of physiological processes, and disruptions of normal circadian biology therefore have the potential to influence a range of disease-related pathways. The genetic basis of circadian rhythms is well studied in model organisms and, more recently, studies of the genetic basis of circadian disorders has confirmed the conservation of key players in circadian biology from invertebrates to humans. In addition, important advances have been made in understanding how these molecules influence physiological functions in tissues throughout the body. Together, these studies set the scene for applying our knowledge of circadian biology to the understanding and treatment of a range of human diseases, including cancer and metabolic and behavioural disorders.

Circadian and CLOCK-controlled regulation of the mouse transcriptome and cell proliferation

Abstract: Circadian rhythms of cell and organismal physiology are controlled by an autoregulatory transcription-translation feedback loop that regulates the expression of rhythmic genes in a tissue-specific manner. Recent studies have suggested that components of the circadian pacemaker, such as the Clock and Per2 gene products, regulate a wide variety of processes, including obesity, sensitization to cocaine, cancer susceptibility, and morbidity to chemotherapeutic agents. To identify a more complete cohort of genes that are transcriptionally regulated by CLOCK and/or circadian rhythms, we used a DNA array interrogating the mouse protein-encoding transcriptome to measure gene expression in liver and skeletal muscle from WT and Clock mutant mice. In WT tissue, we found that a large percentage of expressed genes were transcription factors that were rhythmic in either muscle or liver, but not in both, suggesting that tissue-specific output of the pacemaker is regulated in part by a transcriptional cascade. In comparing tissues from WT and Clock mutant mice, we found that the Clock mutation affects the expression of many genes that are rhythmic in WT tissue, but also profoundly affects many nonrhythmic genes. In both liver and skeletal muscle, a significant number of CLOCK-regulated genes were associated with the cell cycle and cell proliferation. To determine whether the observed patterns in cell-cycle gene expression in Clock mutants resulted in functional dysregulation, we compared proliferation rates of fibroblasts derived from WT or Clock mutant embryos and found that the Clock mutation significantly inhibits cell growth and proliferation.

Identification of the circadian transcriptome in adult mouse skeletal muscle.

Abstract: Circadian rhythms are approximate 24-h behavioral and physiological cycles that function to prepare an organism for daily environmental changes. The basic clock mechanism is a network of transcript...

CLOCK and BMAL1 regulate MyoD and are necessary for maintenance of skeletal muscle phenotype and function

Abstract: MyoD, a master regulator of myogenesis, exhibits a circadian rhythm in its mRNA and protein levels, suggesting a possible role in the daily maintenance of muscle phenotype and function We report that MyoD is a direct target of the circadian transcriptional activators CLOCK and BMAL1, which bind in a rhythmic manner to the core enhancer of the MyoD promoter Skeletal muscle of ClockΔ19 and Bmal1−/− mutant mice exhibited ∼30% reductions in normalized maximal force A similar reduction in force was observed at the single-fiber level Electron microscopy (EM) showed that the myofilament architecture was disrupted in skeletal muscle of ClockΔ19, Bmal1−/−, and MyoD−/− mice The alteration in myofilament organization was associated with decreased expression of actin, myosins, titin, and several MyoD target genes EM analysis also demonstrated that muscle from both ClockΔ19 and Bmal1−/− mice had a 40% reduction in mitochondrial volume The remaining mitochondria in these mutant mice displayed aberrant morphology and increased uncoupling of respiration This mitochondrial pathology was not seen in muscle of MyoD−/− mice We suggest that altered expression of both Pgc-1α and Pgc-1β in ClockΔ19 and Bmal1−/− mice may underlie this pathology Taken together, our results demonstrate that disruption of CLOCK or BMAL1 leads to structural and functional alterations at the cellular level in skeletal muscle The identification of MyoD as a clock-controlled gene provides a mechanism by which the circadian clock may generate a muscle-specific circadian transcriptome in an adaptive role for the daily maintenance of adult skeletal muscle

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

The mammalian circadian timing system: organization and coordination of central and peripheral clocks.

Abstract: Most physiology and behavior of mammalian organisms follow daily oscillations. These rhythmic processes are governed by environmental cues (e.g., fluctuations in light intensity and temperature), an internal circadian timing system, and the interaction between this timekeeping system and environmental signals. In mammals, the circadian timekeeping system has a complex architecture, composed of a central pacemaker in the brain's suprachiasmatic nuclei (SCN) and subsidiary clocks in nearly every body cell. The central clock is synchronized to geophysical time mainly via photic cues perceived by the retina and transmitted by electrical signals to SCN neurons. In turn, the SCN influences circadian physiology and behavior via neuronal and humoral cues and via the synchronization of local oscillators that are operative in the cells of most organs and tissues. Thus, some of the SCN output pathways serve as input pathways for peripheral tissues. Here we discuss knowledge acquired during the past few years on the complex structure and function of the mammalian circadian timing system.

Adverse metabolic and cardiovascular consequences of circadian misalignment

Abstract: Effects of Behavioral Cycle. The effects of the behavioral cycle, independent of the circadian cycle, on leptin, glucose, insulin, epinephrine, norepinephrine, and cortisol are shown in Fig. 2, Left panels. Leptin varied significantly across the behavioral cycle, with a trough around breakfast and a peak after the last meal, coinciding with the onset of the scheduled sleep episode (P 0.001, peak-to-trough 44%). Also, both glucose and insulin varied significantly across the behavioral cycle (glucose: P 0.001, peak-to-trough 26%; insulin: P 0.001, peak-to-trough 158%), presumably the result of the timing of meals. Both epinephrine and norepinephrine varied significantly across the behavioral cycle with peaks during the wake episode and troughs during the sleep episode (epinephrine: P 0.001, peak-totrough 83%; norepinephrine: P 0.001, peak-to-trough 72%). Cortisol varied significantly across the behavioral cycle, peaking after awakening and with a trough at the onset of the scheduled sleep episode (P 0.001, peak-to-trough 38%). Effect of Circadian Cycle. The effects of the circadian cycle, independent of the behavioral cycle, on leptin, glucose, insulin, epinephrine, norepinephrine, and cortisol, are shown in Fig. 2, Right panels. Glucose had a significant endogenous circadian rhythm (P 0.018, peak-to-trough 4%), with a peak during the biological night (circadian bin 300° and 0°; equivalent to22:30– 06:30 in these subjects). Epinephrine exhibited a significant endogenous circadian rhythm (P 0.001, peak-to-trough 53%), with a peak during the biological day (circadian bin 180°; equivalent to 14:30–18:30). Cortisol had a significant endogenous circadian rhythm (P 0.001, peak-to-trough 113%), with a peak at the end of the biological night (60°; close to habitual wake time). There were no significant circadian rhythms in leptin, insulin, or norepinephrine.

Central and Peripheral Circadian Clocks in Mammals

Abstract: The circadian system of mammals is composed of a hierarchy of oscillators that function at the cellular, tissue, and systems levels. A common molecular mechanism underlies the cell-autonomous circadian oscillator throughout the body, yet this clock system is adapted to different functional contexts. In the central suprachiasmatic nucleus (SCN) of the hypothalamus, a coupled population of neuronal circadian oscillators acts as a master pacemaker for the organism to drive rhythms in activity and rest, feeding, body temperature, and hormones. Coupling within the SCN network confers robustness to the SCN pacemaker, which in turn provides stability to the overall temporal architecture of the organism. Throughout the majority of the cells in the body, cell-autonomous circadian clocks are intimately enmeshed within metabolic pathways. Thus, an emerging view for the adaptive significance of circadian clocks is their fundamental role in orchestrating metabolism.

Molecular components of the mammalian circadian clock

Abstract: Mammals synchronize their circadian activity primarily to the cycles of light and darkness in the environment. This is achieved by ocular photoreception relaying signals to the suprachiasmatic nucleus (SCN) in the hypothalamus. Signals from the SCN cause the synchronization of independent circadian clocks throughout the body to appropriate phases. Signals that can entrain these peripheral clocks include humoral signals, metabolic factors, and body temperature. At the level of individual tissues, thousands of genes are brought to unique phases through the actions of a local transcription/translation-based feedback oscillator and systemic cues. In this molecular clock, the proteins CLOCK and BMAL1 cause the transcription of genes which ultimately feedback and inhibit CLOCK and BMAL1 transcriptional activity. Finally, there are also other molecular circadian oscillators which can act independently of the transcription-based clock in all species which have been tested.